{"paper_id":"037ce4d1-e58c-48de-b7f2-189d4ec2c80c","body_text":"The Changes in BRCA Mutation Status and Their Impact on Recurrence in Ovarian Cancer Patients After Oral PARPi Treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Changes in BRCA Mutation Status and Their Impact on Recurrence in Ovarian Cancer Patients After Oral PARPi Treatment Jinwei Liu, Zheng Li, Liwen Zhou, Yingjie Zhu, Yinghai Wang, Yan Hu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6859028/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The present study was designed to investigate the genetic mutations in patients with recurrent ovarian cancer (OC), with a particular focus on comparing the genetic profiles prior to and following relapse in individuals who had previously been treated with Olaparib. Methods This retrospective study enrolled nine patients with OC between November 2017 and October 2023. Eligible patients were required to have histologically confirmed OC, prior BRCA1/2 genetic testing, and a history of receiving Olaparib as maintenance therapy. Patients were subsequently divided into two groups based on the timing of their BRCA1/2 testing. Comprehensive analysis of BRCA1/2 mutations was performed using a combination of sequencing and multiplex ligation-dependent probe amplification (MLPA). Results Among 9 OC patients analyzed, platinum-sensitive recurrence was observed. Frameshift and splice mutations in BRCA1/2 were identified as significant factors associated with disease progression and poor prognosis. Moreover, TP53 alterations were frequently detected in conjunction with FGFR3 or PIK3CA mutations. While PARP inhibitor (PARPi) therapy effectively extended progression-free survival, resistance eventually developed through secondary mutations and activation of bypass repair pathways. Conclusions In OC patiens, BRCA1/2 mutations, encompassing frameshift and splice variants, and copy number losses are linked to higher recurrence rates and reduced progression-free survival (PFS). Extended Olaparib treatment is associated with improved PFS, whereas shorter treatment durations may contribute to the emergence of resistance. Ovarian Cancer BRCA Mutation PARP inhibitor Recurrence Prognosis Figures Figure 1 1. Introduction Ovarian cancer (OC) ranks as the third most frequent malignancy in the female reproductive system, with incidences lower than those of cervical and endometrial cancers. However, it is associated with the highest mortality rate among gynecological cancers[ 1 ]. Historically, the 5-year survival rate for OC was exceedingly low, at approximately 20%[ 2 ]. Recently, significant improvements in survival outcomes have been achieved through therapeutic advancements, including enhanced surgical techniques and the introduction of oral PARP inhibitors (PARPi)[ 3 ]. For instance, studies have demonstrated that niraparib, when used as first-line maintenance therapy, significantly prolongs PFS in patients, particularly those with homologous recombination deficiency, compared to controls[ 4 ]. Additionally, research has highlighted the considerable long-term benefits of Olaparib in the adjuvant treatment of high-risk early breast cancer patients following surgery[ 5 ]. Despite these therapeutic gains, OC continues to exhibit a high recurrence rate, with up to 70% of cases relapsing within 5 years, which remains a primary factor contributing to the low 5-year survival rate[ 6 ]. Pathogenic mutations in the BRCA1 and BRCA2 genes are frequently implicated in hereditary breast and ovarian cancers, contributing to 5–10% of breast cancers and approximately 20% of OC[ 7 , 8 ]. These genes are essential for maintaining genomic integrity, particularly through their role in the homologous recombination repair (HRR) pathway[ 9 ]. Loss-of-function mutations in BRCA1 or BRCA2 result in the accumulation of mutations and genomic rearrangements, which drive tumorigenesis[ 10 ]. Individuals harboring germline BRCA1/2 mutations are at increased risk for not only breast and ovarian cancers but also prostate and pancreatic cancers[ 11 ]. Women with pathogenic BRCA1/2 variants are commonly diagnosed with high-grade serous OC. Additionally, BRCA1 mutation carriers typically present with hormone receptor-negative breast cancer, whereas BRCA2 mutation carriers more often develop hormone receptor-positive breast cancer[ 12 , 13 ]. Despite these insights, patients with OC or triple-negative breast cancer associated with BRCA1/2 mutations frequently relapse within a few years after diagnosis. These relapses are often associated with treatment resistance, rendering recurrent OC and metastatic breast cancer refractory to therapy[ 14 , 15 ]. For OC with BRCA1/2 mutations, the current standard treatment comprises first-line platinum-based chemotherapy, typically involving cisplatin or carboplatin. Meanwhile, PARPi are increasingly employed for maintenance therapy and in the treatment of metastatic disease[ 16 ]. Clinical trials have further shown that PARPi offer substantial clinical benefits in the adjuvant setting[ 17 ]. However, despite these therapeutic advances, tumors with BRCA1/2 mutations often initially respond to platinum agents and PARPi but eventually develop resistance over time[ 18 ]. Preclinical studies have elucidated several mechanisms underlying resistance to platinum agents and PARPi, including the expression of the MDR1 efflux pump and the loss of key DNA damage response regulators such as TP53BP1, REV7, CHD4, and PARP1[ 19 – 21 ]. Notably, in tumors from germline BRCA1/2 mutation carriers, the most common resistance mechanism involves secondary mutations that restore the function of the mutant BRCA1/2 alleles[ 22 ]. Despite substantial progress in treating OC with PARPi, the increasing prevalence of relapse among patients previously treated with PARPi presents significant challenges for subsequent therapeutic strategies. Both reoperation and continued chemotherapy often fail to achieve consistently satisfactory outcomes[ 23 ]. Although surgical intervention can provide survival benefits for some patients with recurrent OC, its efficacy is highly inconsistent across individuals[ 24 ]. Furthermore, while platinum-based chemotherapy remains a cornerstone treatment for patients with platinum-sensitive recurrent OC, the escalating frequency of recurrences and the progressively shorter platinum-free intervals eventually result in the development of platinum resistance in most patients[ 25 ]. The underlying mechanisms of OC recurrence are still not fully elucidated, especially in patients who have previously received PARPi. Emerging evidence indicates that the epithelial-mesenchymal transition (EMT) may be a critical factor in OC recurrence and is associated with drug resistance[ 26 ]. Additionally, alterations in BRCA1/2 mutation status during OC recurrence can impact prognosis[ 27 ]. However, research on the specific mutation sites of BRCA1/2 in recurrent patients is limited, which hampers the accurate prediction of treatment responses in clinical practice. In this retrospective study, we investigated nine patients with OC who had previously undergone BRCA1/2 testing and received maintenance therapy with Olaparib, aiming to elucidate the molecular mechanisms underlying OC recurrence, particularly in patients previously treated with PARPi. Our study included patients who experienced recurrence and subsequently underwent secondary surgical intervention. Tumor tissue samples obtained during surgery were subjected to repeat genetic testing to compare genetic mutation profiles pre- and post-recurrence. By correlating changes in genetic mutation sites with clinical, pathological data, and patient outcomes, we sought to explore the associations between genetic mutation alterations, OC recurrence, Olaparib resistance, and prognosis. Provided clinical evidence supporting the necessity of repeat BRCA1/2 testing in patients with recurrent OC and to inform personalized treatment strategies. 2. Materials and method 2.1 Patients Patients were retrospectively recruited between November 2017 and October 2023 to the Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University). Eligible participants included women aged 18 to 60 years, who were diagnosed with histologically confirmed OC and had previously undergone BRCA1/2 genetic testing and received Olaparib maintenance therapy (n = 9). Patients with non-epithelial OC or incomplete clinical data were excluded from the study. This study was approved by the Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University) under the ethics approval KYLX2025-147, and written informed consent was obtained from all participants prior to the collection of tumor samples and clinical data. The committee has stipulated that the maximal tumor diameter permitted for inclusion in our study is less than 5 cm. All patients included in our study met the inclusion criteria regarding tumor size, and none of the patients exceeded the maximal tumor diameter of 5 cm. 2.2 Study Design and Grouping The patients were divided into two groups based on the timing of BRCA1/2 testing and the use of Olaparib maintenance therapy. Group 1 with 5 patients who underwent BRCA1/2 testing at initial diagnosis and received Olaparib maintenance therapy after completing initial treatment until the first recurrence. These patients underwent secondary cytoreductive surgery at recurrence, and tumor tissues were collected for genetic testing. Group 2 with 4 patients who underwent BRCA1/2 testing after tumor recurrence and received Olaparib maintenance therapy after achieving complete response (CR) or partial response (PR) until the next recurrence. These patients underwent secondary cytoreductive surgery at recurrence, and tumor tissues were collected for genetic testing (Fig. 1 ). All patients received standard OC treatment, with initial chemotherapy based on platinum agents. Comprehensive germ-line and tumor tissue testing for BRCA1/2 mutations were performed in a certified diagnostic pathology laboratory using sequencing and multiplex ligation-dependent probe amplification (MLPA). Specifically, for genetic sequencing, we used the specific sequencing platform Illumina NovaSeq 6000 with a specific sequencing depth 300× coverage to ensure high accuracy and reliability. For MLPA, we utilized the specific MLPA kit MRC-Holland MLPA kit P087-B1 BRCA1/2 following the manufacturer’s instructions. The demographics, tumor markers, pathological features, treatment information, and PFS were collected for both groups. Patients were followed up via telephone or outpatient visits to obtain treatment outcomes and survival status. 3. Results 3.1 Study population Table 1 summarizes the clinical characteristics of patients in Group 1, who had an initial diagnosis age ranging from 34 to 55 years. All patients were histologically confirmed to have high-grade serous adenocarcinoma following initial surgery and were classified as stage IIIC based on the International Federation of Gynecology and Obstetrics (FIGO) staging system[ 28 ]. They received first-line chemotherapy with carboplatin and paclitaxel. Subsequently, maintenance therapy with Olaparib was administered for 7 to 22 months, until disease recurrence occurred approximately 24 months after treatment initiation. All patients experienced platinum-sensitive recurrence, with the number of recurrent lesions ranging from single to multiple. Common sites of recurrence included the abdominal cavity (n = 2), pelvic lymph nodes (n = 1), brain (n = 1), and liver parenchyma (n = 1). One patient had multifocal recurrence involving the stomach and abdominal lymph nodes. Table 1 Basic information of patients in group 1. ID Age Pathological Type FIGO Chemotherapy Recurrence site Oral Olaparib (month) Platinum sensitive recurrence 1303162 55 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Liver 22 Yes 1312286 39 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Gastric and abdominal lymph nodes 15 Yes 1287469 55 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Multiple abdominal metastases, retroperitoneal lymph nodes 9 Yes 1327593 34 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Brain 7 Yes 1335145 44 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Multiple metastases in abdominal cavity and pelvic cavity 8 Yes In Group 2, we included four patients whose ages at the time of initial diagnosis ranged from 39 to 50 years. The timing of their initial genetic testing was highly variable, with the majority (n = 3) undergoing their first genetic analysis during second-line treatment, while one patient had initial testing during sixth-line treatment. The interval between the first and second genetic tests was inconsistent, with the second analysis performed between the third and seventh lines of treatment. Histopathological evaluations revealed diverse tumor subtypes, including moderately to poorly differentiated serous papillary adenocarcinoma (n = 1), serous papillary adenocarcinoma (n = 1), and high-grade serous adenocarcinoma (n = 2). Disease staging, according to the FIGO system, varied widely, with cases distributed across stage I (n = 1), stage IIIb (n = 1), and stage IIIC (n = 2). The duration of Olaparib maintenance therapy ranged from 2 to 33 months. Notably, two patients initiated Olaparib treatment only during third-line therapy. All patients in this group experienced platinum-sensitive recurrence. Regarding recurrence patterns, 75% of patients (n = 3) had multifocal recurrence involving multiple anatomical sites, while the remaining 25% (n = 1) had isolated liver recurrence (Table 2 ). Table 2 Basic information of patients in group 2. ID Age Pathological Type FIGO Chemotherapy Recurrence site Oral Olaparib (month) Platinum sensitive recurrence 1201712 53 Moderately poorly differentiated serous papillary adenocarcinoma IIIC Paclitaxel + Carboplatin Multiple metastases in abdominal cavity and pelvic cavity 33 Yes 1172832 39 Serous papillary adenocarcinoma I Paclitaxel + Carboplatin Multiple metastases in descending colon, abdominal cavity and pelvis 2 Yes 1385307 50 High-grade serous adenocarcinoma IIIC Paclitaxel + Carboplatin Multiple metastases in ascending colon, abdominal cavity and pelvis 13 Yes 1141256 50 Low-grade differentiated serous adenocarcinoma IIIB Paclitaxel + Carboplatin Liver 24 Yes 3.2 Genomic Analyses in Primary and Recurrent Ovarian Cancer Cases Mutations detected in both primary and recurrent tumor samples were categorized into somatic and germline types, indicating whether they originated from tumor cells or inherited genetic material. In Group 1, a nonsense mutation (p.Q12*) was consistently identified in both primary and recurrent samples. Most mutations were localized to exons 2, 10, 11 and 15 of the BRCA1 gene. Recurrent tumors generally retained the same exon mutations observed in primary tumors but exhibited additional genomic changes. These included frameshift mutations such as c.66_67insA and c.2799del, which cause protein truncation and may impair BRCA1’s DNA repair function. The point mutation (p.Q12*) introduced a premature stop codon, leading to a nonfunctional protein (Table 3 ). Table 3 Genetic mutations of group 1 patients. ID Detection time Mutation type Mutation gene Variation site Nucleotide alteration Amino acid change Functional change 1303162 Primary Somatic cell BRCA1 exon15 c.4541del p.S1514Lfs*34 Frameshift mutation Recrudescence Somatic cell BRCA1 exon15 c.4541del p.S1514Lfs*34 Frameshift mutation 1312286 Primary Somatic cell BRCA1 exon2 c.34C > T p.Q12* Point mutation Recrudescence Somatic cell BRCA1 exon2 c.34C > T p.Q12* Point mutation 1287469 Primary Blood BRCA1 exon2 c.66_67insA p.E23Rfs*18 Frameshift mutation Recrudescence Somatic cell BRCA1 exon2 c.66_67insA p.E23Rfs*18 Frameshift mutation 1327593 Primary Blood BRCA1 exon11 c.2799del p.(Q934Rfs*66) Frameshift mutation Recrudescence Somatic cell BRCA1 exon10 c.2799del p.(Q934Rfs*66) Frameshift mutation 1335145 Primary Blood BRCA1 exon11 c.2695del p.(V899Sfs*101) Frameshift mutation Recrudescence Somatic cell BRCA1 exon10 c.2695del p.(V899Sfs*101) Frameshift mutation As detailed in Table 4 , the primary mutated genes identified in Group 2 were BRCA1 and BRCA2. BRCA1 mutations were predominantly located in exon 10, intron 5 and exon 2, while BRCA2 mutations were largely confined to exon 10. The most common nucleotide alterations in BRCA1 included c.213-2A > G, c.3329dup, and c.53T > C. In BRCA2, the most frequent nucleotide change was c.1886_1887dup. These mutations resulted in specific amino acid changes, such as p.Q1111Afs*4 and p.M18T in BRCA1, and p.T630Lfs*15 in BRCA2. The primary functional consequences were frameshift and point mutations, both of which significantly compromised protein function. Notably, these mutations were detected across various stages of recurrence, ranging from second-line to seventh-line treatments. Table 4 Genetic mutations of group 2 patients. ID Detection time Mutation type Mutation gene Variation site Nucleotide alteration Amino acid change Functional change 1201712 Second-line Blood BRCA2 exon10 c.1886_1887dup p.T630Lfs*15 Frameshift mutation Four-line Somatic cell BRCA2 exon10 c.1886_1887dup p.T630Lfs*15 Frameshift mutation 1172832 Six-line Somatic cell BRCA1 intron5 c.213-2A > G - Splicing mutation Seven-line Somatic cell BRCA1 intron5 c.213-2A > G - Splicing mutation 1385307 Second-line Blood BRCA1 exon10 c.3329dup p.Q1111Afs*4 Frameshift mutation Third-line Somatic cell BRCA1 exon10 c.3329dup p.Q1111Afs*4 Frameshift mutation 1141256 Second-line Blood BRCA1 exon2 c.53T > C p.M18T Point mutation Four-line Somatic cell BRCA1 exon2 c.53T > C p.M18T Point mutation 3.3 Recurrence Patterns and Genetic Mutations Table 5 provides an overview of the recurrence patterns and genetic mutations identified in the study. BRCA1 frameshift mutations were commonly associated with OC recurrence and adverse outcomes, characterized by elevated recurrence rates and reduced PFS. Patients with decreased BRCA1 copy numbers exhibited a higher risk of recurrence. In contrast, those harboring point mutations experienced fewer recurrences and longer PFS compared to those with frameshift mutations. The intervals between recurrences were highly variable, with PFS ranging from 3 to 34 months. Similarly, BRCA2 frameshift mutations were linked to recurrence and poor prognosis, particularly after multiple lines of treatment. Lower BRCA2 copy numbers were associated with worse outcomes, marked by shorter PFS (9–23 months). Notably, BRCA1 splice site mutations were associated with particularly short PFS (3 months). Reduced BRCA1/2 copy numbers were frequently observed in patients with recurrent disease and those who had undergone multiple therapies, resulting in significantly shorter PFS. Additionally, tumor cells that accumulated additional mutations following multiple therapies may develop resistance to PARPi. Although BRCA1/2 frameshift mutations generally confer sensitivity to PARPi, patients receiving prolonged Olaparib treatment often exhibited longer PFS. Table 5 Relationship between gene mutation and relapse times. ID Mutation gene Variation site Nucleotide alteration Amino acid change Genes with reduced copy numbers Recurrence times Oral Olaparib (month) PFS 1303162 BRCA1 exon15 c.4541del p.S1514Lfs*34 - 2 22 23 BRCA1 exon15 c.4541del p.S1514Lfs*34 BRCA2 1312286 BRCA1 exon2 c.34C > T p.Q12* - 2 15 16 BRCA1 exon2 c.34C > T p.Q12* - 1287469 BRCA1 exon2 c.66_67insA p.E23Rfs*18 - 2 9 14 BRCA1 exon2 c.66dup p.E23Rfs*18 BRCA1, BRCA2 1327593 BRCA1 exon11 c.2799del p.(Q934Rfs*66) - 1 7 9 BRCA1 exon10 c.2799del p.(Q934Rfs*66) BRCA1 1335145 BRCA1 exon11 c.2695del p.(V899Sfs*101) - 1 8 9 BRCA1 exon10 c.2695del p.(V899Sfs*101) BRCA1 1201712 BRCA2 exon10 c.1886_1887dup p.T630Lfs*15 - 3 33 34 BRCA2 exon10 c.1886_1887dup p.T630Lfs*15 BRCA2 1172832 BRCA1 intron5 c.213-2A > G - - 6 2 3 BRCA1 Intron5 c.213-2A > G - BRCA1, BRCA2 1385307 BRCA1 exon10 c.3329dup p.Q1111Afs*4 - 2 13 16 BRCA1 exon10 c.3329dup p.Q1111Afs*4 - 1141256 BRCA1 exon2 c.53T > C p.M18T - 2 24 25 BRCA1 exon2 c.53T > C p.M18T BRCA1 3.4 TP53 Mutations and Co-occurring Genetic Alterations TP53 mutations were detected at a high frequency in tissue samples, particularly in tumor tissues. Specific mutations were commonly identified and associated with tumor progression and recurrence. In contrast, TP53 mutations were rarely detected in blood samples. In some cases, TP53 mutations remained stable across multiple testing timepoints (e.g., exon7 c.742C > T; p.R248W and exon5 c.527G > A; p.C176Y), suggesting that these mutations may act as driver mutations in tumorigenesis. In other cases, new TP53 mutations emerged during subsequent testing (e.g., exon5 c.383del; p.P128Lfs*42), indicating the accumulation of additional mutations during tumor progression. Notably, TP53 mutations frequently co-occurred with FGFR3 copy number gains, suggesting a potential synergistic role of FGFR3 and TP53 in driving tumor progression. Additionally, PIK3CA copy number gains were found alongside TP53 mutations, potentially implicating activation of the PI3K/AKT/mTOR pathway in tumorigenesis (Table 6 ). Table 6 TP53 genetic changes in patients. ID Variation site Nucleotide alteration Amino acid change Genes with reduced copy numbers 1303162 exon7 c.742C > T p.R248W - exon7 c.742C > T p.R248W FGFR3 1312286 exon5 c.527G > A p.C176Y - exon5 c.527G > A p.C176Y - 1287469 - - - - exon5 c.383del p.P128Lfs*42 FGFR3 1327593 - - - - exon6 c.659A > G p.Y220C FGFR3 1335145 - - - - exon6 c.659A > G p.Y220C - 1201712 - - - - exon5 c.536A > G p.H179R FGFR3, PIK3CA 1172832 - c.215C > G p.P72R - - c.376-1G > A - - 1385307 exon6 c.586C > T p.R196 - exon6 c.586C > T p.R196 - 1141256 - - - - exon8 c.838A > G p.R280g - 4. Discussion OC is characterized by significant genetic complexity, with approximately 10% of cases being associated with hereditary genetic mutations[ 29 ]. Among these hereditary cases, mutations in the BRCA1 and BRCA2 genes, which play crucial roles in the HRR pathway, are major contributors to the development of OC. BRCA1 mutations are often present throughout the disease course, from the primary diagnosis to recurrence. BRCA1/2 mutations impair DNA repair mechanisms, resulting in genomic instability and increased sensitivity to DNA-damaging agents[ 30 ]. These genetic alterations disrupt the HRR pathway and render cancer cells more susceptible to therapies that induce DNA double-strand breaks, such as PARPi. In recurrent OC, copy number loss and loss of heterozygosity can lead to haploinsufficiency, which is a critical factor in treatment resistance. These mutations often result in truncated or non-functional proteins, further destabilizing the genome and promoting resistance to therapy[ 31 ]. Multiple studies have highlighted the link between BRCA1/2 frameshift mutations and heightened tumor aggressiveness and recurrence rates. These frameshift and splice site mutations frequently produce truncated or non-functional proteins, which in turn cause HRR deficiencies and genomic instability. Such genomic instability not only fuels tumor progression but also enhances vulnerability to DNA-damaging agents, such as PARPi[ 32 ]. When these mutations persist in recurrent disease, they may trigger resistance mechanisms, including secondary mutations or copy number changes, that undermine the effectiveness of PARPi therapy. This can lead to more severe HRR defects, accelerated tumor evolution, and shorter PFS. Conversely, patients with point mutations usually experience milder functional disruptions and retain partial HRR capacity, resulting in longer PFS and fewer recurrences[ 33 , 34 ]. However, these studies did not fully explore the relationship between mutations and recurrence, determine the optimal timing for genetic testing, or clarify the dynamic nature of BRCA1/2 mutation status during disease progression and its impact on PARPi resistance. In our study, mutations were most frequently identified in exons 2, 10, 11 and 15 of the BRCA1 gene. Recurrent tumors typically maintained the same exonic mutations as the primary tumors but exhibited additional genomic alterations, including the introduction of premature termination codons. Patients with BRCA1 frameshift mutations and copy number reductions had higher recurrence rates and shorter PFS. Similarly, patients harboring BRCA2 frameshift mutations experienced more frequent recurrences and a worse prognosis after multiple lines of treatment. These findings are consistent with previous studies demonstrating that BRCA1/2 mutations, particularly frameshift and copy number variations, are associated with increased genomic instability and resistance to treatment[ 35 , 36 ]. In addition to identifying specific genomic alterations, such as large deletions affecting critical functional domains of BRCA1, we also detected mutations in other genes. TP53 mutations are a key factor in OC progression. TP53, a crucial tumor suppressor gene, is frequently mutated in OC, with most mutations occurring in the DNA-binding domain[ 37 ]. These mutations typically result in loss of function or reduced activity of the TP53 protein, thereby promoting tumorigenesis and progression[ 38 ]. Frameshift and splice site mutations in TP53 lead to truncated or non-functional proteins and can dynamically change over time, with some mutations remaining stable while others emerge or disappear. This dynamic nature contributes to tumor heterogeneity and evolution[ 39 ]. In our study, TP53 mutations were frequently co-occurrent with other genetic alterations, such as FGFR3 copy number gain and PIK3CA copy number increase, driving tumor recurrence and progression in patients. The coexistence of TP53 mutations with BRCA1/2 mutations may exacerbate genomic instability and accelerate tumor evolution. The TP53 mutations observed in our study likely intensified genomic instability and impacted treatment response, consistent with the findings that TP53 mutations are associated with poor prognosis and resistance to chemotherapy in OC patients[ 40 ]. The comprehensive analysis of BRCA1/2 mutation status across multiple lines of therapy reveals distinct mutation types and provides insights into their evolution and impact on disease trajectory and outcomes. Early genetic testing at the primary tumor stage can identify patients who may benefit from targeted therapies; BRCA1/2 mutation carriers are typically more sensitive to these agents, and early intervention can markedly improve treatment outcomes. However, in recurrent settings, changes in BRCA1/2 mutation status, such as copy number loss or the emergence of new mutations, may contribute to resistance to PARPi and diminished treatment efficacy. Several limitations of our study should be acknowledged. Notably, the sample size, particularly in Group 2, may limit the generalizability of our findings. Additionally, the retrospective nature of the study introduces potential biases in data collection and analysis. Future prospective studies with larger cohorts are needed to validate our findings and explore the mechanisms underlying PARPi resistance and genetic mutations in greater detail. Future research should focus on elucidating the mechanisms of PARPi resistance, particularly the roles of secondary mutations, copy number alterations, and epigenetic modifications. The interplay between BRCA1/2 mutations and other genetic alterations, such as TP53 mutations, warrants further investigation. In summary, the integration of genetic testing into clinical practice has revolutionized the management of OC. The identification of BRCA1/2 and TP53 mutations, along with their dynamic changes over time, provides valuable insights into tumor biology and treatment response. The complexity of genomic alterations and the development of resistance mechanisms highlight the need for ongoing research to identify new therapeutic targets and optimize treatment approaches. Personalized therapeutic strategies guided by comprehensive genetic profiling hold promise for improving outcomes in patients with OC. 5. Conclusion Our study investigated the changes in BRCA mutation status in OC patients following oral PARPi treatment and their impact on disease recurrence. The primary findings revealed that BRCA1/2 frameshift mutations, splice site mutations, and copy number losses are associated with a higher risk of OC recurrence and shorter PFS. In contrast, point mutations were linked to a lower recurrence risk and longer PFS. Additionally, patients with prolonged Olaparib treatment durations exhibited extended PFS, suggesting sustained sensitivity to PARP inhibition, while shorter treatment durations were associated with potential resistance. These findings underscore the critical role of BRCA1/2 mutation status in OC prognosis and treatment decision-making, particularly in the context of PARPi therapy. Abbreviations OC ovarian cancer MLPA multiplex ligation-dependent probe amplification PARPi PARP inhibitor PFS progression-free survival EMT epithelial-mesenchymal transition CR complete response PR partial response FIGO international federation of gynecology and obstetrics HRR homologous recombination repair Declarations Acknowledgments ： Not applicable. Research ethics ： The study was conducted in accordance with the Declaration of Helsinki. The research protocol was approved by the Ethics Committee of Yunnan Cancer Hospital (Ethic Approval Number: KYLX2025-147), and all of the participants provided signed informed consent. Author contributions: JWL, ZL- conceptualization, writing-original draft, investigation, analysis, resources. LWZ, YJZ, YHW, YH, LZ, YQR, YL- analysis, resources. XLY- supervision, conceptualization, methodology, writing-review and editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Conflicts of Interest: The author states no conflict of interest. Research funding: None declared. Data Availability : The raw data can be obtained on request from the corresponding author. References Mazidimoradi A, Momenimovahed Z, Allahqoli L, Tiznobaik A, Hajinasab N, Salehiniya H, et al. The global, regional and national epidemiology, incidence, mortality, and burden of ovarian cancer. Health Sci Rep. 2022;5:e936. https://doi.org/10.1002/hsr2.936 . Wei YF, Ning L, Xu YL, Ma J, Li DR, Feng ZF, et al. Worldwide patterns and trends in ovarian cancer incidence by histological subtype: a population-based analysis from 1988 to 2017. EClinicalMedicine. 2025;79:102983. https://doi.org/10.1016/j.eclinm.2024.102983 . Onji H, Murai J. 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Lancet Oncol. 2022;23:465–78. https://doi.org/10.1016/s1470-2045(22)00122-x . Giannini A, Di Dio C, Di Donato V, D'Oria O, Salerno MG, Capalbo G, et al. PARP Inhibitors in Newly Diagnosed and Recurrent Ovarian Cancer. Am J Clin Oncol. 2023;46:414–9. https://doi.org/10.1097/coc.0000000000001024 . Masvidal Hernandez M, Cros Costa S, Salvador Coloma C, Quilez Cutillas A, Barretina-Ginesta MP, Cotes Sanchís A. First-line PARP inhibitor maintenance treatment in ovarian carcinoma for older adult women: a review of the current literature. Clin Transl Oncol. 2025;27:417–24. https://doi.org/10.1007/s12094-024-03609-y . Li L, Gu Y, Zhang M, Shi X, Li Z, Xu X, et al. HRD effects on first-line adjuvant chemotherapy and PARPi maintenance therapy in Chinese ovarian cancer patients. NPJ Precis Oncol. 2023;7:51. https://doi.org/10.1038/s41698-023-00402-y . Summey R, Uyar D. Ovarian cancer resistance to PARPi and platinum-containing chemotherapy. Cancer Drug Resist. 2022;5:637–46. https://doi.org/10.20517/cdr.2021.146 . Biegała Ł, Gajek A, Marczak A, Rogalska A. PARP inhibitor resistance in ovarian cancer: Underlying mechanisms and therapeutic approaches targeting the ATR/CHK1 pathway. Biochim Biophys Acta Rev Cancer. 2021;1876:188633. https://doi.org/10.1016/j.bbcan.2021.188633 . Calheiros J, Corbo V, Saraiva L. Overcoming therapeutic resistance in pancreatic cancer: Emerging opportunities by targeting BRCAs and p53. Biochim Biophys Acta Rev Cancer. 2023;1878:188914. https://doi.org/10.1016/j.bbcan.2023.188914 . Zaman N, Kushwah AS, Badriprasad A, Chakraborty G. Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency. Int Rev Cell Mol Biol. 2024;389:257–301. https://doi.org/10.1016/bs.ircmb.2024.03.004 . Murciano-Goroff YR, Schram AM, Rosen EY, Won H, Gong Y, Noronha AM, et al. Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies. Nat Commun. 2022;13:7182. https://doi.org/10.1038/s41467-022-34109-8 . Ngu SF, Ngan HY, Chan KK. Role of adjuvant and post-surgical treatment in gynaecological cancer. Best Pract Res Clin Obstet Gynaecol. 2022;78:2–13. https://doi.org/10.1016/j.bpobgyn.2021.09.001 . Baek MH, Park EY, Ha HI, Park SY, Lim MC, Fotopoulou C, et al. Secondary Cytoreductive Surgery in Platinum-Sensitive Recurrent Ovarian Cancer: A Meta-Analysis. J Clin Oncol. 2022;40:1659–70. https://doi.org/10.1200/jco.21.02085 . Miras I, Estévez-García P, Muñoz-Galván S. Clinical and molecular features of platinum resistance in ovarian cancer. Crit Rev Oncol Hematol. 2024;201:104434. https://doi.org/10.1016/j.critrevonc.2024.104434 . Shao M, Gao Y, Xu X, Chan DW, Du J. Exosomes: Key Factors in Ovarian Cancer Peritoneal Metastasis and Drug Resistance. Biomolecules. 2024;14. https://doi.org/10.3390/biom14091099 . Afrăsânie VA, Rusu A, Gheorghe AS, Froicu EM, Dumitrescu EA, Gafton B, et al. Long-Term Survival in BRCA1 Mutant Advanced Ovarian Cancer: Unveiling the Impact of Olaparib. Diagnostics (Basel). 2024;14. https://doi.org/10.3390/diagnostics14171898 . Mor-Hadar D, Wilailak S, Berek J, McNally OM. FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy. Int J Gynaecol Obstet. 2024;167:976–80. https://doi.org/10.1002/ijgo.15884 . Murawski M, Jagodziński A, Bielawska-Pohl A, Klimczak A. Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications. Cells. 2024;13. https://doi.org/10.3390/cells13040345 . Voutsadakis IA, Stravodimou A. Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes Besides BRCA1 and BRCA2 as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies. Anticancer Res. 2023;43:967–81. https://doi.org/10.21873/anticanres.16241 . Shao C, Chang MS, Lam FC, Marley AR, Tang H, Song Y et al. A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer. J Oncol. 2022; 2022: 5830475. https://doi.org/10.1155/2022/5830475 Shao C, Wan J, Lam FC, Tang H, Marley AR, Song Y, et al. A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies. Environ Mol Mutagen. 2022;63:308–16. https://doi.org/10.1002/em.22505 . Bhamidipati D, Haro-Silerio JI, Yap TA, Ngoi N. PARP inhibitors: enhancing efficacy through rational combinations. Br J Cancer. 2023;129:904–16. https://doi.org/10.1038/s41416-023-02326-7 . Brabson JP, Leesang T, Yap YS, Wang J, Lam MQ, Fang B, et al. Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia. Cell Rep. 2023;42:112027. https://doi.org/10.1016/j.celrep.2023.112027 . Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016;2:482–90. https://doi.org/10.1001/jamaoncol.2015.5495 . Walsh PL, Bothe JR, Bhardwaj S, Hu M, Nofsinger R, Xia B, et al. A canine biorelevant dissolution method for predicting in vivo performance of orally administered sustained release matrix tablets. Drug Dev Ind Pharm. 2016;42:836–44. https://doi.org/10.3109/03639045.2015.1082583 . Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022;13:974. https://doi.org/10.1038/s41419-022-05408-1 . Biatta CM, Paudice M, Greppi M, Parrella V, Parodi A, De Luca G, et al. The fading guardian: clinical relevance of TP53 null mutation in high-grade serous ovarian cancers. Front Immunol. 2023;14:1221605. https://doi.org/10.3389/fimmu.2023.1221605 . Wallis B, Bowman KR, Lu P, Lim CS. The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer. Biomolecules. 2023;13. https://doi.org/10.3390/biom13010159 . Ghezelayagh TS, Pennington KP, Norquist BM, Khasnavis N, Radke MR, Kilgore MR, et al. Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations. Gynecol Oncol. 2021;160:786–92. https://doi.org/10.1016/j.ygyno.2020.12.007 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6859028\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":482901910,\"identity\":\"8f927a96-d747-4530-8ae1-72691b6cf7e8\",\"order_by\":0,\"name\":\"Jinwei Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital 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04:53:13\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6859028/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6859028/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":86663754,\"identity\":\"6f75f52a-23a6-45cc-81f4-53e0de852faf\",\"added_by\":\"auto\",\"created_at\":\"2025-07-14 10:51:02\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":58291,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe STROBE flow chart of patients.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6859028/v1/ff6ad9bfbe23f1eda9f55097.png\"},{\"id\":89486802,\"identity\":\"2afa6d70-7016-4d47-959b-ade21d21cb20\",\"added_by\":\"auto\",\"created_at\":\"2025-08-20 13:02:12\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1137362,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6859028/v1/19c878ec-9061-45f3-8045-a5e3e34c7ee9.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"The Changes in BRCA Mutation Status and Their Impact on Recurrence in Ovarian Cancer Patients After Oral PARPi Treatment\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eOvarian cancer (OC) ranks as the third most frequent malignancy in the female reproductive system, with incidences lower than those of cervical and endometrial cancers. However, it is associated with the highest mortality rate among gynecological cancers[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Historically, the 5-year survival rate for OC was exceedingly low, at approximately 20%[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Recently, significant improvements in survival outcomes have been achieved through therapeutic advancements, including enhanced surgical techniques and the introduction of oral PARP inhibitors (PARPi)[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. For instance, studies have demonstrated that niraparib, when used as first-line maintenance therapy, significantly prolongs PFS in patients, particularly those with homologous recombination deficiency, compared to controls[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Additionally, research has highlighted the considerable long-term benefits of Olaparib in the adjuvant treatment of high-risk early breast cancer patients following surgery[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Despite these therapeutic gains, OC continues to exhibit a high recurrence rate, with up to 70% of cases relapsing within 5 years, which remains a primary factor contributing to the low 5-year survival rate[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003ePathogenic mutations in the BRCA1 and BRCA2 genes are frequently implicated in hereditary breast and ovarian cancers, contributing to 5\\u0026ndash;10% of breast cancers and approximately 20% of OC[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. These genes are essential for maintaining genomic integrity, particularly through their role in the homologous recombination repair (HRR) pathway[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. Loss-of-function mutations in BRCA1 or BRCA2 result in the accumulation of mutations and genomic rearrangements, which drive tumorigenesis[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. Individuals harboring germline BRCA1/2 mutations are at increased risk for not only breast and ovarian cancers but also prostate and pancreatic cancers[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. Women with pathogenic BRCA1/2 variants are commonly diagnosed with high-grade serous OC. Additionally, BRCA1 mutation carriers typically present with hormone receptor-negative breast cancer, whereas BRCA2 mutation carriers more often develop hormone receptor-positive breast cancer[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Despite these insights, patients with OC or triple-negative breast cancer associated with BRCA1/2 mutations frequently relapse within a few years after diagnosis. These relapses are often associated with treatment resistance, rendering recurrent OC and metastatic breast cancer refractory to therapy[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eFor OC with BRCA1/2 mutations, the current standard treatment comprises first-line platinum-based chemotherapy, typically involving cisplatin or carboplatin. Meanwhile, PARPi are increasingly employed for maintenance therapy and in the treatment of metastatic disease[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Clinical trials have further shown that PARPi offer substantial clinical benefits in the adjuvant setting[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. However, despite these therapeutic advances, tumors with BRCA1/2 mutations often initially respond to platinum agents and PARPi but eventually develop resistance over time[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. Preclinical studies have elucidated several mechanisms underlying resistance to platinum agents and PARPi, including the expression of the MDR1 efflux pump and the loss of key DNA damage response regulators such as TP53BP1, REV7, CHD4, and PARP1[\\u003cspan additionalcitationids=\\\"CR20\\\" citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Notably, in tumors from germline BRCA1/2 mutation carriers, the most common resistance mechanism involves secondary mutations that restore the function of the mutant BRCA1/2 alleles[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eDespite substantial progress in treating OC with PARPi, the increasing prevalence of relapse among patients previously treated with PARPi presents significant challenges for subsequent therapeutic strategies. Both reoperation and continued chemotherapy often fail to achieve consistently satisfactory outcomes[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Although surgical intervention can provide survival benefits for some patients with recurrent OC, its efficacy is highly inconsistent across individuals[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Furthermore, while platinum-based chemotherapy remains a cornerstone treatment for patients with platinum-sensitive recurrent OC, the escalating frequency of recurrences and the progressively shorter platinum-free intervals eventually result in the development of platinum resistance in most patients[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. The underlying mechanisms of OC recurrence are still not fully elucidated, especially in patients who have previously received PARPi. Emerging evidence indicates that the epithelial-mesenchymal transition (EMT) may be a critical factor in OC recurrence and is associated with drug resistance[\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Additionally, alterations in BRCA1/2 mutation status during OC recurrence can impact prognosis[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. However, research on the specific mutation sites of BRCA1/2 in recurrent patients is limited, which hampers the accurate prediction of treatment responses in clinical practice.\\u003c/p\\u003e\\u003cp\\u003eIn this retrospective study, we investigated nine patients with OC who had previously undergone BRCA1/2 testing and received maintenance therapy with Olaparib, aiming to elucidate the molecular mechanisms underlying OC recurrence, particularly in patients previously treated with PARPi. Our study included patients who experienced recurrence and subsequently underwent secondary surgical intervention. Tumor tissue samples obtained during surgery were subjected to repeat genetic testing to compare genetic mutation profiles pre- and post-recurrence. By correlating changes in genetic mutation sites with clinical, pathological data, and patient outcomes, we sought to explore the associations between genetic mutation alterations, OC recurrence, Olaparib resistance, and prognosis. Provided clinical evidence supporting the necessity of repeat BRCA1/2 testing in patients with recurrent OC and to inform personalized treatment strategies.\\u003c/p\\u003e\"},{\"header\":\"2. Materials and method\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.1 Patients\\u003c/h2\\u003e\\u003cp\\u003ePatients were retrospectively recruited between November 2017 and October 2023 to the Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University). Eligible participants included women aged 18 to 60 years, who were diagnosed with histologically confirmed OC and had previously undergone BRCA1/2 genetic testing and received Olaparib maintenance therapy (n\\u0026thinsp;=\\u0026thinsp;9). Patients with non-epithelial OC or incomplete clinical data were excluded from the study. This study was approved by the Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University) under the ethics approval KYLX2025-147, and written informed consent was obtained from all participants prior to the collection of tumor samples and clinical data. The committee has stipulated that the maximal tumor diameter permitted for inclusion in our study is less than 5 cm. All patients included in our study met the inclusion criteria regarding tumor size, and none of the patients exceeded the maximal tumor diameter of 5 cm.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003e2.2 Study Design and Grouping\\u003c/h3\\u003e\\n\\u003cp\\u003eThe patients were divided into two groups based on the timing of BRCA1/2 testing and the use of Olaparib maintenance therapy. Group 1 with 5 patients who underwent BRCA1/2 testing at initial diagnosis and received Olaparib maintenance therapy after completing initial treatment until the first recurrence. These patients underwent secondary cytoreductive surgery at recurrence, and tumor tissues were collected for genetic testing. Group 2 with 4 patients who underwent BRCA1/2 testing after tumor recurrence and received Olaparib maintenance therapy after achieving complete response (CR) or partial response (PR) until the next recurrence. These patients underwent secondary cytoreductive surgery at recurrence, and tumor tissues were collected for genetic testing (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eAll patients received standard OC treatment, with initial chemotherapy based on platinum agents. Comprehensive germ-line and tumor tissue testing for BRCA1/2 mutations were performed in a certified diagnostic pathology laboratory using sequencing and multiplex ligation-dependent probe amplification (MLPA). Specifically, for genetic sequencing, we used the specific sequencing platform Illumina NovaSeq 6000 with a specific sequencing depth 300\\u0026times; coverage to ensure high accuracy and reliability. For MLPA, we utilized the specific MLPA kit MRC-Holland MLPA kit P087-B1 BRCA1/2 following the manufacturer\\u0026rsquo;s instructions. The demographics, tumor markers, pathological features, treatment information, and PFS were collected for both groups. Patients were followed up via telephone or outpatient visits to obtain treatment outcomes and survival status.\\u003c/p\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e3.1 Study population\\u003c/h2\\u003e\\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e summarizes the clinical characteristics of patients in Group 1, who had an initial diagnosis age ranging from 34 to 55 years. All patients were histologically confirmed to have high-grade serous adenocarcinoma following initial surgery and were classified as stage IIIC based on the International Federation of Gynecology and Obstetrics (FIGO) staging system[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. They received first-line chemotherapy with carboplatin and paclitaxel. Subsequently, maintenance therapy with Olaparib was administered for 7 to 22 months, until disease recurrence occurred approximately 24 months after treatment initiation. All patients experienced platinum-sensitive recurrence, with the number of recurrent lesions ranging from single to multiple. Common sites of recurrence included the abdominal cavity (n\\u0026thinsp;=\\u0026thinsp;2), pelvic lymph nodes (n\\u0026thinsp;=\\u0026thinsp;1), brain (n\\u0026thinsp;=\\u0026thinsp;1), and liver parenchyma (n\\u0026thinsp;=\\u0026thinsp;1). One patient had multifocal recurrence involving the stomach and abdominal lymph nodes.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eBasic information of patients in group 1.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"8\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eAge\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ePathological Type\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eFIGO\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eChemotherapy\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eRecurrence site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eOral Olaparib (month)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePlatinum sensitive recurrence\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1303162\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e55\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eLiver\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e22\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1312286\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e39\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eGastric and abdominal lymph nodes\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1287469\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e55\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eMultiple abdominal metastases, retroperitoneal lymph nodes\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1327593\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e34\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBrain\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1335145\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e44\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eMultiple metastases in abdominal cavity and pelvic cavity\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eIn Group 2, we included four patients whose ages at the time of initial diagnosis ranged from 39 to 50 years. The timing of their initial genetic testing was highly variable, with the majority (n\\u0026thinsp;=\\u0026thinsp;3) undergoing their first genetic analysis during second-line treatment, while one patient had initial testing during sixth-line treatment. The interval between the first and second genetic tests was inconsistent, with the second analysis performed between the third and seventh lines of treatment. Histopathological evaluations revealed diverse tumor subtypes, including moderately to poorly differentiated serous papillary adenocarcinoma (n\\u0026thinsp;=\\u0026thinsp;1), serous papillary adenocarcinoma (n\\u0026thinsp;=\\u0026thinsp;1), and high-grade serous adenocarcinoma (n\\u0026thinsp;=\\u0026thinsp;2). Disease staging, according to the FIGO system, varied widely, with cases distributed across stage I (n\\u0026thinsp;=\\u0026thinsp;1), stage IIIb (n\\u0026thinsp;=\\u0026thinsp;1), and stage IIIC (n\\u0026thinsp;=\\u0026thinsp;2). The duration of Olaparib maintenance therapy ranged from 2 to 33 months. Notably, two patients initiated Olaparib treatment only during third-line therapy. All patients in this group experienced platinum-sensitive recurrence. Regarding recurrence patterns, 75% of patients (n\\u0026thinsp;=\\u0026thinsp;3) had multifocal recurrence involving multiple anatomical sites, while the remaining 25% (n\\u0026thinsp;=\\u0026thinsp;1) had isolated liver recurrence (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eBasic information of patients in group 2.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"8\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eAge\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ePathological Type\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eFIGO\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eChemotherapy\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eRecurrence site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eOral Olaparib (month)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePlatinum sensitive recurrence\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1201712\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e53\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eModerately poorly differentiated serous papillary adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eMultiple metastases in abdominal cavity and pelvic cavity\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e33\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1172832\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e39\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSerous papillary adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eI\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eMultiple metastases in descending colon, abdominal cavity and pelvis\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1385307\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e50\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eHigh-grade serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIC\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eMultiple metastases in ascending colon, abdominal cavity and pelvis\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e13\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1141256\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e50\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eLow-grade differentiated serous adenocarcinoma\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIIIB\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePaclitaxel\\u0026thinsp;+\\u0026thinsp;Carboplatin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eLiver\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e24\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003e3.2 Genomic Analyses in Primary and Recurrent Ovarian Cancer Cases\\u003c/h3\\u003e\\n\\u003cp\\u003eMutations detected in both primary and recurrent tumor samples were categorized into somatic and germline types, indicating whether they originated from tumor cells or inherited genetic material. In Group 1, a nonsense mutation (p.Q12*) was consistently identified in both primary and recurrent samples. Most mutations were localized to exons 2, 10, 11 and 15 of the BRCA1 gene. Recurrent tumors generally retained the same exon mutations observed in primary tumors but exhibited additional genomic changes. These included frameshift mutations such as c.66_67insA and c.2799del, which cause protein truncation and may impair BRCA1\\u0026rsquo;s DNA repair function. The point mutation (p.Q12*) introduced a premature stop codon, leading to a nonfunctional protein (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eGenetic mutations of group 1 patients.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"8\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eDetection time\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMutation type\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eMutation gene\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eVariation site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eNucleotide alteration\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eAmino acid change\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFunctional change\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1303162\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003ePrimary\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.4541del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.S1514Lfs*34\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eRecrudescence\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.4541del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.S1514Lfs*34\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1312286\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003ePrimary\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.34C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.Q12*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePoint mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eRecrudescence\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.34C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.Q12*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePoint mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1287469\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003ePrimary\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.66_67insA\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.E23Rfs*18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eRecrudescence\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.66_67insA\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.E23Rfs*18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1327593\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003ePrimary\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.2799del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.(Q934Rfs*66)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eRecrudescence\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.2799del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.(Q934Rfs*66)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1335145\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003ePrimary\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.2695del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.(V899Sfs*101)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eRecrudescence\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.2695del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.(V899Sfs*101)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eAs detailed in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e, the primary mutated genes identified in Group 2 were BRCA1 and BRCA2. BRCA1 mutations were predominantly located in exon 10, intron 5 and exon 2, while BRCA2 mutations were largely confined to exon 10. The most common nucleotide alterations in BRCA1 included c.213-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G, c.3329dup, and c.53T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C. In BRCA2, the most frequent nucleotide change was c.1886_1887dup. These mutations resulted in specific amino acid changes, such as p.Q1111Afs*4 and p.M18T in BRCA1, and p.T630Lfs*15 in BRCA2. The primary functional consequences were frameshift and point mutations, both of which significantly compromised protein function. Notably, these mutations were detected across various stages of recurrence, ranging from second-line to seventh-line treatments.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eGenetic mutations of group 2 patients.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"8\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eDetection time\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMutation type\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eMutation gene\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eVariation site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eNucleotide alteration\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eAmino acid change\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFunctional change\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1201712\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSecond-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.1886_1887dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.T630Lfs*15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eFour-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.1886_1887dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.T630Lfs*15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1172832\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSix-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eintron5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.213-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eSplicing mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSeven-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eintron5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.213-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eSplicing mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1385307\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSecond-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.3329dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.Q1111Afs*4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eThird-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.3329dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.Q1111Afs*4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eFrameshift mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1141256\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSecond-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBlood\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.53T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.M18T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePoint mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eFour-line\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSomatic cell\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003ec.53T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep.M18T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003ePoint mutation\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e3.3 Recurrence Patterns and Genetic Mutations\\u003c/h2\\u003e\\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e provides an overview of the recurrence patterns and genetic mutations identified in the study. BRCA1 frameshift mutations were commonly associated with OC recurrence and adverse outcomes, characterized by elevated recurrence rates and reduced PFS. Patients with decreased BRCA1 copy numbers exhibited a higher risk of recurrence. In contrast, those harboring point mutations experienced fewer recurrences and longer PFS compared to those with frameshift mutations. The intervals between recurrences were highly variable, with PFS ranging from 3 to 34 months. Similarly, BRCA2 frameshift mutations were linked to recurrence and poor prognosis, particularly after multiple lines of treatment. Lower BRCA2 copy numbers were associated with worse outcomes, marked by shorter PFS (9\\u0026ndash;23 months). Notably, BRCA1 splice site mutations were associated with particularly short PFS (3 months). Reduced BRCA1/2 copy numbers were frequently observed in patients with recurrent disease and those who had undergone multiple therapies, resulting in significantly shorter PFS. Additionally, tumor cells that accumulated additional mutations following multiple therapies may develop resistance to PARPi. Although BRCA1/2 frameshift mutations generally confer sensitivity to PARPi, patients receiving prolonged Olaparib treatment often exhibited longer PFS.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab5\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 5\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eRelationship between gene mutation and relapse times.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"9\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eMutation gene\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eVariation site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eNucleotide alteration\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eAmino acid change\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eGenes with reduced copy numbers\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eRecurrence times\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eOral Olaparib (month)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003ePFS\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1303162\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.4541del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.S1514Lfs*34\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e22\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e23\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.4541del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.S1514Lfs*34\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1312286\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.34C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.Q12*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e16\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.34C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.Q12*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1287469\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.66_67insA\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.E23Rfs*18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e14\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.66dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.E23Rfs*18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA1, BRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1327593\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.2799del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.(Q934Rfs*66)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e9\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.2799del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.(Q934Rfs*66)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1335145\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.2695del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.(V899Sfs*101)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e9\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.2695del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.(V899Sfs*101)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1201712\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.1886_1887dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.T630Lfs*15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e33\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e34\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.1886_1887dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.T630Lfs*15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1172832\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eintron5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.213-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e3\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eIntron5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.213-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA1, BRCA2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1385307\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.3329dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.Q1111Afs*4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e13\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e16\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.3329dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.Q1111Afs*4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1141256\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.53T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.M18T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e24\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e25\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eexon2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ec.53T\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep.M18T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eBRCA1\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003e3.4 TP53 Mutations and Co-occurring Genetic Alterations\\u003c/h3\\u003e\\n\\u003cp\\u003eTP53 mutations were detected at a high frequency in tissue samples, particularly in tumor tissues. Specific mutations were commonly identified and associated with tumor progression and recurrence. In contrast, TP53 mutations were rarely detected in blood samples. In some cases, TP53 mutations remained stable across multiple testing timepoints (e.g., exon7 c.742C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T; p.R248W and exon5 c.527G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A; p.C176Y), suggesting that these mutations may act as driver mutations in tumorigenesis. In other cases, new TP53 mutations emerged during subsequent testing (e.g., exon5 c.383del; p.P128Lfs*42), indicating the accumulation of additional mutations during tumor progression. Notably, TP53 mutations frequently co-occurred with FGFR3 copy number gains, suggesting a potential synergistic role of FGFR3 and TP53 in driving tumor progression. Additionally, PIK3CA copy number gains were found alongside TP53 mutations, potentially implicating activation of the PI3K/AKT/mTOR pathway in tumorigenesis (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab6\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 6\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eTP53 genetic changes in patients.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"5\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eID\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eVariation site\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eNucleotide alteration\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eAmino acid change\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eGenes with reduced copy numbers\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1303162\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.742C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.R248W\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.742C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.R248W\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eFGFR3\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1312286\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.527G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.C176Y\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.527G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.C176Y\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1287469\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.383del\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.P128Lfs*42\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eFGFR3\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1327593\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.659A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.Y220C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eFGFR3\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1335145\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.659A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.Y220C\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1201712\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.536A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.H179R\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eFGFR3, PIK3CA\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1172832\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.215C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.P72R\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.376-1G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1385307\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.586C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.R196\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.586C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.R196\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003e1141256\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eexon8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.838A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003ep.R280g\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e-\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cp\\u003eOC is characterized by significant genetic complexity, with approximately 10% of cases being associated with hereditary genetic mutations[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]. Among these hereditary cases, mutations in the BRCA1 and BRCA2 genes, which play crucial roles in the HRR pathway, are major contributors to the development of OC. BRCA1 mutations are often present throughout the disease course, from the primary diagnosis to recurrence. BRCA1/2 mutations impair DNA repair mechanisms, resulting in genomic instability and increased sensitivity to DNA-damaging agents[\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. These genetic alterations disrupt the HRR pathway and render cancer cells more susceptible to therapies that induce DNA double-strand breaks, such as PARPi. In recurrent OC, copy number loss and loss of heterozygosity can lead to haploinsufficiency, which is a critical factor in treatment resistance. These mutations often result in truncated or non-functional proteins, further destabilizing the genome and promoting resistance to therapy[\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eMultiple studies have highlighted the link between BRCA1/2 frameshift mutations and heightened tumor aggressiveness and recurrence rates. These frameshift and splice site mutations frequently produce truncated or non-functional proteins, which in turn cause HRR deficiencies and genomic instability. Such genomic instability not only fuels tumor progression but also enhances vulnerability to DNA-damaging agents, such as PARPi[\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. When these mutations persist in recurrent disease, they may trigger resistance mechanisms, including secondary mutations or copy number changes, that undermine the effectiveness of PARPi therapy. This can lead to more severe HRR defects, accelerated tumor evolution, and shorter PFS. Conversely, patients with point mutations usually experience milder functional disruptions and retain partial HRR capacity, resulting in longer PFS and fewer recurrences[\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]. However, these studies did not fully explore the relationship between mutations and recurrence, determine the optimal timing for genetic testing, or clarify the dynamic nature of BRCA1/2 mutation status during disease progression and its impact on PARPi resistance.\\u003c/p\\u003e\\u003cp\\u003eIn our study, mutations were most frequently identified in exons 2, 10, 11 and 15 of the BRCA1 gene. Recurrent tumors typically maintained the same exonic mutations as the primary tumors but exhibited additional genomic alterations, including the introduction of premature termination codons. Patients with BRCA1 frameshift mutations and copy number reductions had higher recurrence rates and shorter PFS. Similarly, patients harboring BRCA2 frameshift mutations experienced more frequent recurrences and a worse prognosis after multiple lines of treatment. These findings are consistent with previous studies demonstrating that BRCA1/2 mutations, particularly frameshift and copy number variations, are associated with increased genomic instability and resistance to treatment[\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]. In addition to identifying specific genomic alterations, such as large deletions affecting critical functional domains of BRCA1, we also detected mutations in other genes. TP53 mutations are a key factor in OC progression. TP53, a crucial tumor suppressor gene, is frequently mutated in OC, with most mutations occurring in the DNA-binding domain[\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]. These mutations typically result in loss of function or reduced activity of the TP53 protein, thereby promoting tumorigenesis and progression[\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e]. Frameshift and splice site mutations in TP53 lead to truncated or non-functional proteins and can dynamically change over time, with some mutations remaining stable while others emerge or disappear. This dynamic nature contributes to tumor heterogeneity and evolution[\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e]. In our study, TP53 mutations were frequently co-occurrent with other genetic alterations, such as FGFR3 copy number gain and PIK3CA copy number increase, driving tumor recurrence and progression in patients. The coexistence of TP53 mutations with BRCA1/2 mutations may exacerbate genomic instability and accelerate tumor evolution. The TP53 mutations observed in our study likely intensified genomic instability and impacted treatment response, consistent with the findings that TP53 mutations are associated with poor prognosis and resistance to chemotherapy in OC patients[\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThe comprehensive analysis of BRCA1/2 mutation status across multiple lines of therapy reveals distinct mutation types and provides insights into their evolution and impact on disease trajectory and outcomes. Early genetic testing at the primary tumor stage can identify patients who may benefit from targeted therapies; BRCA1/2 mutation carriers are typically more sensitive to these agents, and early intervention can markedly improve treatment outcomes. However, in recurrent settings, changes in BRCA1/2 mutation status, such as copy number loss or the emergence of new mutations, may contribute to resistance to PARPi and diminished treatment efficacy. Several limitations of our study should be acknowledged. Notably, the sample size, particularly in Group 2, may limit the generalizability of our findings. Additionally, the retrospective nature of the study introduces potential biases in data collection and analysis. Future prospective studies with larger cohorts are needed to validate our findings and explore the mechanisms underlying PARPi resistance and genetic mutations in greater detail. Future research should focus on elucidating the mechanisms of PARPi resistance, particularly the roles of secondary mutations, copy number alterations, and epigenetic modifications. The interplay between BRCA1/2 mutations and other genetic alterations, such as TP53 mutations, warrants further investigation. In summary, the integration of genetic testing into clinical practice has revolutionized the management of OC. The identification of BRCA1/2 and TP53 mutations, along with their dynamic changes over time, provides valuable insights into tumor biology and treatment response. The complexity of genomic alterations and the development of resistance mechanisms highlight the need for ongoing research to identify new therapeutic targets and optimize treatment approaches. Personalized therapeutic strategies guided by comprehensive genetic profiling hold promise for improving outcomes in patients with OC.\\u003c/p\\u003e\"},{\"header\":\"5. Conclusion\",\"content\":\"\\u003cp\\u003e Our study investigated the changes in BRCA mutation status in OC patients following oral PARPi treatment and their impact on disease recurrence. The primary findings revealed that BRCA1/2 frameshift mutations, splice site mutations, and copy number losses are associated with a higher risk of OC recurrence and shorter PFS. In contrast, point mutations were linked to a lower recurrence risk and longer PFS. Additionally, patients with prolonged Olaparib treatment durations exhibited extended PFS, suggesting sustained sensitivity to PARP inhibition, while shorter treatment durations were associated with potential resistance. These findings underscore the critical role of BRCA1/2 mutation status in OC prognosis and treatment decision-making, particularly in the context of PARPi therapy.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv id=\\\"AGS1\\\" class=\\\"AbbreviationGroupSection\\\"\\u003e\\u003cdiv class=\\\"Heading\\\"\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionList\\\"\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eOC\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eovarian cancer\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eMLPA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003emultiplex ligation-dependent probe amplification\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003ePARPi\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003ePARP inhibitor\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003ePFS\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eprogression-free survival\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eEMT\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eepithelial-mesenchymal transition\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eCR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003ecomplete response\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003ePR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003epartial response\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eFIGO\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003einternational federation of gynecology and obstetrics\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eHRR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003ehomologous recombination repair\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003cstrong\\u003e：\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResearch ethics\\u003c/strong\\u003e\\u003cstrong\\u003e：\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was conducted in accordance with the Declaration of Helsinki. The research protocol was approved by the Ethics Committee of Yunnan Cancer Hospital (Ethic Approval Number: KYLX2025-147), and all of the participants provided signed informed consent.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eJWL, ZL- conceptualization, writing-original draft, investigation, analysis, resources. LWZ, YJZ, YHW, YH, LZ, YQR, YL- analysis, resources. XLY- supervision, conceptualization, methodology, writing-review and editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflicts of Interest:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe author states no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResearch funding:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNone declared.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData Availability\\u003c/strong\\u003e\\u003cstrong\\u003e:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe raw data can be obtained on request from the corresponding author.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eMazidimoradi A, Momenimovahed Z, Allahqoli L, Tiznobaik A, Hajinasab N, Salehiniya H, et al. The global, regional and national epidemiology, incidence, mortality, and burden of ovarian cancer. 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Gynecol Oncol. 2021;160:786\\u0026ndash;92. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/j.ygyno.2020.12.007\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.ygyno.2020.12.007\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Ovarian Cancer, BRCA Mutation, PARP inhibitor, Recurrence, Prognosis\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6859028/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6859028/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e\\u003cp\\u003eThe present study was designed to investigate the genetic mutations in patients with recurrent ovarian cancer (OC), with a particular focus on comparing the genetic profiles prior to and following relapse in individuals who had previously been treated with Olaparib.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eThis retrospective study enrolled nine patients with OC between November 2017 and October 2023. Eligible patients were required to have histologically confirmed OC, prior BRCA1/2 genetic testing, and a history of receiving Olaparib as maintenance therapy. Patients were subsequently divided into two groups based on the timing of their BRCA1/2 testing. Comprehensive analysis of BRCA1/2 mutations was performed using a combination of sequencing and multiplex ligation-dependent probe amplification (MLPA).\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eAmong 9 OC patients analyzed, platinum-sensitive recurrence was observed. Frameshift and splice mutations in BRCA1/2 were identified as significant factors associated with disease progression and poor prognosis. Moreover, TP53 alterations were frequently detected in conjunction with FGFR3 or PIK3CA mutations. While PARP inhibitor (PARPi) therapy effectively extended progression-free survival, resistance eventually developed through secondary mutations and activation of bypass repair pathways.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e\\u003cp\\u003eIn OC patiens, BRCA1/2 mutations, encompassing frameshift and splice variants, and copy number losses are linked to higher recurrence rates and reduced progression-free survival (PFS). Extended Olaparib treatment is associated with improved PFS, whereas shorter treatment durations may contribute to the emergence of resistance.\\u003c/p\\u003e\",\"manuscriptTitle\":\"The Changes in BRCA Mutation Status and Their Impact on Recurrence in Ovarian Cancer Patients After Oral PARPi Treatment\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-14 10:42:58\",\"doi\":\"10.21203/rs.3.rs-6859028/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"586c6e89-65ef-4d95-b4bf-4d3bd3b3d5eb\",\"owner\":[],\"postedDate\":\"July 14th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-08-20T12:54:00+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-07-14 10:42:58\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6859028\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6859028\",\"identity\":\"rs-6859028\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}