Multigene germline and somatic testing for epithelial ovarian cancer in China

Multigene germline and somatic testing for epithelial ovarian cancer in China | 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 Article Multigene germline and somatic testing for epithelial ovarian cancer in China Lei Li, Jianwei Zhang, Nan Song, Bao Sun, Depu Zhang, Yi Li, Yunong Gao, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6493572/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Aug, 2025 Read the published version in npj Precision Oncology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Targeted sequencing has proven invaluable in evaluating BRCA1/2 and homologous recombination repair (HR) pathway genes in epithelial ovarian cancer (EOC). Comprehensive analysis of germline and somatic HR-related gene variants is critical to understanding their clinical significance. This study aims to explore the significance of such variants in Chinese EOC patients. Materials and Methods We analyzed 229 EOC patients using a 21-gene ovarian cancer panel and 141 patients with a 508-gene pan-cancer panel. Germline and somatic variants in the 21 HR-related genes were identified and interpreted. Variant frequencies were calculated, and overall survival (OS) and progression-free survival (PFS) were compared between carriers and non-carriers of BRCA1, BRCA2, and HR-related gene mutations. Responses to platinum-based chemotherapy and the PARP inhibitor Niraparib were also assessed. Results Among the 229 patients, 17.9% carried BRCA1 mutations, 3.5% carried BRCA2 mutations, and 23.1% had mutations in HR-related genes. TP53 was the most common somatic mutation (66.4%). When both germline and somatic mutations were included, BRCA1 and BRCA2 mutation rates rose to 23.6% and 6.1%, respectively. Survival analyses (n=200) showed significantly longer OS for BRCA1/2 and HR-related mutation carriers (germline+somatic) compared to non-carriers under "LP+" (pathogenic/likely pathogenic variants) and "VUS+" (including variants of uncertain significance). Improved OS was observed for BRCA2 mutation carriers and BRCA1/2 somatic mutation carriers under VUS+ strategies. The hazard ratio for OS was lower in the VUS+ group, indicating enhanced predictive performance. Conclusions BRCA1/2 and HR-related mutations are associated with improved OS and sensitivity to therapy. Integrating germline, somatic, and VUS data enhances survival prediction and treatment guidance, underscoring the need for comprehensive genetic assessments in EOC management. Biological sciences/Genetics/Cancer genetics Health sciences/Diseases/Cancer/Gynaecological cancer/Ovarian cancer Germline BRCA 1/2 mutations Epithelial ovarian cancer (EOC) Homologous recombination (HR) repair Germline and somatic variants Overall survival (OS) Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Ovarian cancer (OC) is one of the leading causes of female cancer worldwide. According to GLOBOCAN 2020 [ 1 ], there were 313,959 new cases and 207,252 deaths globally. In China, the incidence of OC has shown a stable increase from approximately 52,100 cases in 2015 to 57,090 cases in 2022, with an alarming rise in death cases from about 22,500 in 2015 to 39,306 in 2022 [ 2 – 4 ]. OC exhibits the highest mortality rate among female cancers, with a five-year survival rate of only 38.9% [ 5 ]. Epithelial ovarian cancer (EOC) represents the majority (approximately 60%) of OC cases [ 8 ], with about 22–25% of EOC attributed to the inheritance of germline mutations in cancer predisposing genes [ 9 , 10 ]. Ovarian cancer predisposing genes include BRCA1 , BRCA2 , other homologous recombination repair (HR) genes [ 11 ], mismatch repair (MMR) genes [ 12 ], and ovarian cancer-related tumor suppressor genes such as TP53 [ 13 ]. Guidelines from the National Comprehensive Cancer Network (NCCN) emphasize the importance of screening high-risk populations for OC and BC predisposition genes, as this provides carriers with opportunities to reduce their OC and BC risks [ 14 , 15 ]. Individuals carrying BRCA1/2 and other high or moderate penetrance genes, should consider clinical interventions such as regular physical examinations, mammograms or MRI scans, and risk-reducing surgeries such as risk-reducing salpingo-oophorectomy (RRSO) [ 16 ]. Furthermore, patients with ovarian cancer who carry BRCA1/2 or other HR-related genes can potentially benefit from platinum-based agents and PARP inhibitors based on genetic testing results [ 17 – 23 ]. BRCA1/2 genes have also demonstrated value in prognosis prediction, as several studies suggest that BRCA1/2 carriers may experience longer survival times [ 24 ]. There is a considerable diversity of mutations in BRCA1 , BRCA2 , and other genes observed in different populations, indicating the need for comprehensive studies worldwide [ 20 , 22 , 25 , 26 ]. While germline mutation spectrum studies have been conducted in Chinese populations, the mutation spectrum in Chinese populations differs from that of Western populations [ 27 – 29 ]. In contrast, there are relatively few reports on the somatic mutation spectrum [ 30 , 31 ]. Since deleterious mutations often indicate pathogenic or likely pathogenic alterations, variants of uncertain significance, which are less harmful, have received less attention [ 32 , 33 ]. There remains a lack of systematic evaluation regarding the overall impact of all HR-related gene mutations on drug sensitivity and prognosis in EOC patients. In this study, we present a comprehensive analysis of the germline and somatic mutation spectra in HR-related genes in Chinese ovarian cancer patients. Our primary objective is to explore the correlations between these mutations, drug sensitivity, and prognosis, thereby shedding light on potential implications for clinical management and treatment strategies. MATERIALS AND METHODS Ethics approval and patient recruitment Prior to participation, all patients provided informed consent after being fully informed about the study. The study was conducted in accordance with ethical principles and guidelines. A total of 1411 ovarian cancer patients were recruited for this study during February 24, 2017 and December 31, 2018. After excluding 1182 patients based on our criteria, a total of 229 patients were included for analysis. ( Supplementary Fig. 1 ). These patients received standard treatment and underwent genetic testing. Clinical information, including age, pathological subtype, stage, tumor size and site, and family history, was collected for analysis. ( Supplementary Table 1 ) Treatment and pathological evaluation. Patients were diagnosed with epithelial ovarian cancer (EOC) through core needle biopsy, laparoscopic biopsy, or debulking surgeries. Debulking surgeries, consisting of primary or interval surgeries combined with platinum-based chemotherapy, were performed following established guidelines [ 15 ]. Sensitivity to platinum-based chemotherapy was determined based on the following criteria: sensitive or resistant, indicating recurrence beyond or within 6 months after the completion of standard chemotherapy, respectively; refractory, indicating recurrence within 4 weeks after the completion of standard chemotherapy or disease progression during the chemotherapy duration. Follow-up was conducted until June 1, 2022, with recurrence and/or progression defined as the appearance of new lesions confirmed by imaging evaluation or histology, or increased tumor markers as identified by physicians. Mortality information was obtained from case reports and/or death certificates. A centralized pathological evaluation was conducted by two independent pathologists to ensure consistency in the assessment of histological subtypes and modification of International Federation of Gynecology and Obstetrics (FIGO) stages. The analysis of drug sensitivity and survival outcomes specifically focused on high-grade serous carcinoma (HGSC) and clear cell/endometrioid subtypes, as different histological types are characterized by distinct mutational spectra [ 34 – 36 ]. Sample preparation and sequencing DNA extraction from ovarian cancer tissue and blood samples of patients was performed using the Qiagen DNA Mini Kit (Qiagen, Hilden, Germany). The DNA quantity and integrity were assessed using the Qubit Fluorometer (Life Technologies). Qualified DNA samples were subjected to capture-based targeted sequencing using the QseqT ovarian cancer panel (21 genes) or the OseqT pan-cancer panel (508 genes), followed by library construction for the BGISEQ-500 platform. Each sample generated sequencing data with an average sequencing depth of over 500x and target region coverage exceeding 99%. Variants calling and data interpretation. The sequencing reads were filtered using SOAPnuke 1.5 and aligned to the hg19 reference genome using BWA 0.7.12. Germline and somatic variants were called using GATK 3.4 following the GATK best practice. Single nucleotide variants (SNVs) were called using GATK Unified Genotyper, while indels were called using GATK Haplotype. All variants were filtered based on quality depth, mapping quality, strand bias, and read position. Variant classification Variants were annotated using ANNOVAR. The focus of variant interpretation was on 21 genes, including 11 homologous recombination repair (HR) related genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD50 , and RAD51C ), 5 mismatch repair related genes ( MLH1, MSH2, MSH6, PMS1 , and PMS2 ), and 5 ovarian cancer related genes ( CDH1, MUTYH, PTEN, STK11 , and TP53 ). Germline variants were classified into five categories according to the recommendations of the American College of Medical Genetics (ACMG): pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). Somatic variants were classified into four categories following the guidelines of the Association for Molecular Pathology (AMP): tier I (variants with strong clinical significance), tier II (variants with potential clinical significance), tier III (variants of unknown clinical significance), and tier IV (variants deemed benign or likely benign). To ensure consistency between germline and somatic variants, tier I, tier II, and tier III were considered equivalent to P, LP, and VUS, respectively, while tier IV corresponded to B and LB. Variants classified as P or LP were confirmed using quantitative polymerase chain reaction (qPCR) or Sanger sequencing. The interpretation of certain variants was updated in 2022 based on updated literature evidence. Variant details are included in Supplementary Tables 2 and 3 . Statistical analysis All statistical analyses were performed using R 3.5.1. The significance of the association between mutation prevalence and clinical characteristics was assessed using an appropriate method (Chi-square test or Fisher exact test) based on the number of cases. Survival curves were plotted according to the Kaplan-Meier method and compared by the log-rank test. Multivariable analysis of progression-free survival and overall survival was conducted using the Cox regression model. RESULTS Recruitment and clinical information A total of 229 ovarian cancer patients were recruited for this study, all of whom underwent panel sequencing of 21 genes. Among them, 141 patients also received panel sequencing of 508 cancer-related genes. The median age of the patients was 55, ranging from 24 to 62 years. The majority of patients (194, 84.7%) had the pathological subtype of High-grade serous ovarian cancer (HGSOC), while the remaining subtypes included Clear Cell Carcinoma (CCC), Endometrioid Carcinoma (EC), Low-grade serous ovarian cancer (LGSOC), Mucinous Carcinoma (MC), SCC, mixed carcinoma, and unspecific carcinoma. Approximately 21% (48/229) of the patients were in the early stage (I or II), while 79% (181/229) were in the late stage (III or IV). It is worth noting that 42.4% (97/229) of the patients had a family history of cancer. All patients received chemotherapy, and 26 of them also received additional PARP inhibitor treatment (Table 1 ). Table 1 Clinicopathological characteristics of the EOC patients. Characteristics 508 genes panel cohort (N = 141) 21 genes panel cohort (N = 229) Age Median (IQR), years 54.0 (48.0, 62.0) 55.0 (48.0, 62.0) Distribution, no. (%) < 50 42 (29.8) 72 (31.4) ≥ 50 99 (70.2) 157 (68.6) Histology, no. (%) Serous 125 (88.7) 200 (87.3) HGSC 122 (86.5) 194 (84.7) LGSC 3 (2.1) 6 (2.6) Clear cell 7 (5.0) 13 (5.7) Endometrioid 4 (2.8) 7 (3.1) Mucinous 1 (0.7) 3 (1.3) Other† 4 (2.8) 6 (2.6) FIGO stage, no. (%) I 12 (8.5) 21 (9.2) II 19 (13.5) 27 (11.8) III 90 (63.8) 148 (64.6) IV 20 (14.2) 33 (14.4) Cancer site, no. (%) Ovary 128 (90.8) 214 (93.4) Fallopian tube 8 (5.7) 9 (3.9) Peritoneum 5 (3.5) 6 (2.6) Disease status at panel testing, no. (%) Primary 126 (89.4) 201 (87.8) Recurrent 15 (10.6) 28 (12.2) Response to platinum-based chemotherapy, no./total no. (%) Sensitive 117/139 (84.2) 190/227 (83.7) Resistant 20/139 (14.4) 30/227 (13.2) Refractory 2/139 (1.4) 7/227 (3.1) Initial chemotherapy with bevacizumab - Yes, no./total no. (%) 13/74 (17.6) 17/138 (12.3) PARPi therapy - Yes, no./total no. (%) 21/124 (16.9) 26/207 (12.6) PFS status - Recurrence/Progression, no./total no. (%) 107/140 (76.4) 183/228 (80.3) OS status - Death, no./total no. (%) 46/140 (32.9) 83/228 (36.4) Personal history of cancer - Yes, no. (%) 7 (5.0) 15 (6.6) Personal history of breast cancer - Yes, no. (%) 2 (1.4) 9 (3.9) Family history of cancer - Yes, no. (%) 60 (42.6) 97 (42.4) Family history of cancer for HBOC testing - Yes, no. (%)‡ 12 (8.5) 20 (8.7) Abbreviations: EOC, epithelial ovarian cancer; IQR, interquartile range; HGSC/LGSC, high/low-grade serous carcinoma; FIGO, International Federation of Gynecology and Obstetrics; PFS, progression-free survival; OS, overall survival; HBOC, hereditary breast and ovarian cancer. †Other EOC histological subtypes include mixed carcinoma (508: n = 2, 21: n = 3), squamous carcinoma (21: n = 1), carcinosarcoma (508: n = 2, 21: n = 2). ‡Family history of cancer for HBOC testing criteria was according to NCCN Guidelines for “Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 1.2015”. Somatic Mutation landscape in 141 patients Somatic single nucleotide variants (SNVs) and insertions/deletions (Indels) were detected through panel sequencing of both the 21 genes and the 508 genes panel. Among the 141 patients who underwent Oseq-T pan-cancer panel sequencing, TP53 mutations were observed in 72% of patients, followed by BRCA1 mutations in 11% of patients, BRCA2 mutations in 6% of patients, and PIK3CA mutations in 10% of patients (Supplementary Fig. 2A) . Within the PIK3CA mutations, specific mutations such as p.E542K, p.E545K, and p.H1047R were detected in 2, 2, and 3 patients, respectively (Supplementary Fig. 2B) . Additionally, mutations in ARID1A (7% of patients), and NF1 (5% of patients) were also identified. In our cohort of 229 patients, a significant proportion (23.6%, 54/229) exhibited the presence of germline pathogenic or likely pathogenic variants in 21 genes, while 29.7% (68/229) carried variants of uncertain significance (VUS). Specifically, 17.9% of patients carried BRCA1 mutations, 3.5% carried BRCA2 mutations, and 23.1% carried mutations in HR-related genes (Fig. 1 A, G). Among these genes, a total of 56 mutations were identified, with BRCA1 (73.2%, 41), BRCA2 (14.3%, 8), and PALB2 (3.6%, 2) being the most prevalent (Fig. 1 A). Furthermore, 98.2% (55/56) of the mutations were harbored in homologous recombination repair (HR) genes, while 1.8% (1/56) occurred in STK11 (Fig. 1 B). The main mutation types observed in BRCA1 and BRCA2 were both frameshift mutations (Fig. 1 C). Regarding somatic mutations, 66.4% of patients carried pathogenic or likely pathogenic level mutations (Tier I and II). Among the 207 somatic mutations identified, 73.9% (153) were deleterious mutations in TP53 , 6.3% (13) in BRCA1 , and 3.4% (7) in BRCA2 (Fig. 1 D). Additionally, 8.7% (18) of the deleterious mutations were found in other HR-related genes (Fig. 1 E). The main mutation type observed in TP53 was missense mutations (Fig. 1 F). By considering both germline and somatic pathogenic or likely pathogenic variants, the carrier rates of deleterious BRCA1 and BRCA2 mutations increased to 23.6% and 6.1%, respectively. Moreover, 35.4% of patients carried at least one germline/somatic deleterious variants in HR-related genes (Fig. 1 G). Ovarian cancer Susceptibility Gene and Prognosis To assess the clinical significance of variants of uncertain significance (VUS), we implemented two distinct classification strategies. The initial approach, referred to as "LP+" classification, involved categorizing carriers with germline pathogenic or likely pathogenic variants and somatic Tier I/II variants as having deleterious mutations, while the remaining patients were classified as non-pathogenic. The second strategy, known as "VUS+" classification, expanded upon the LP + classification by including germline VUS and somatic Tier III variants as additional deleterious mutations. Carriers were assigned to the mutation group (Mut, means VUS+/Tier III+), while non-carriers were classified as the wildtype group (WT). Survival analyses were conducted to compare the outcomes of carriers with germline, somatic, and germline + somatic variants using the LP+/VUS + strategy. Only 200 patients were included in survival analysis ( Supplementary Table 4 ). Univariate analysis revealed that under the LP + grouping strategy, patients with deleterious mutations in BRCA1/2 and HR-related genes (somatic + germline) exhibited prolonged overall survival (OS) (Fig. 2 A for HR, Supplementary Fig. 3A for BRCA1/2 , p-value: 0.016, 0.027), and a similar but non-significant trend was observed in progression-free survival (PFS) (Fig. 2 D for HR, Supplementary Fig. 3B for BRCA1/2 , p-value: 0.071, 0.16) compared to non-carriers. In the VUS + grouping strategy, carriers of HR related genes (Fig. 2 B), BRCA2 ( Supplementary Fig. 3C ) and BRCA1/2 (Fig. 2 C) deleterious mutations (somatic + germline) demonstrated extended OS (p-value: 0.002, 0.018, and 0.006, respectively) compared to non-carriers. A similar trend was observed in PFS, although the log-rank test did not reach statistical significance (Fig. 2 E for HR, Supplementary Fig. 3D for BRCA2 and Fig. 2 F for BRCA1/2 , p-value: 0.099, 0.1, and 0.41, respectively). Notably, carriers of somatic BRCA1/2 mutations exhibited significantly longer OS than non-carriers ( Supplementary Fig. 3F, p -value: 0.047). However, BRCA1 mutations did not significantly impact survival time in terms of OS or PFS under either classification strategy. Subsequently, we conducted multivariate survival analysis, adjusting for age, histology, and FIGO stage. In both the LP + and VUS + groups, carriers of germline + somatic HR-related mutations demonstrated prolonged OS (Fig. 3 A; LP+: p-value = 0.005, VUS+: p-value < 0.001) and PFS (Fig. 3 B; LP+: p-value = 0.018, VUS+: p-value = 0.009). Moreover, germline + somatic BRCA1/2 carriers exhibited extended OS (Fig. 3 A; LP+: p-value = 0.011, VUS+: p-value = 0.002). The hazard ratio of BRCA1/2 and HR-related mutation carriers in the VUS + group was lower than in the LP + group (Fig. 3 ). For BRCA1/2 , the hazard ratio of OS was 0.46 (95% CI: 0.25–0.84) in the LP + group and 0.41 (95% CI: 0.24–0.72) in the VUS + group. For HR, the hazard ratio of OS was 0.46 (95% CI: 0.26–0.79) in the LP + group and 0.43 (95% CI: 0.26–0.70) in the VUS + group. The hazard ratio of PFS was 0.66 (95% CI: 0.47–0.93) in the LP + group and 0.65 (95% CI: 0.47–0.90) in the VUS + group. Notably, only in the VUS + group, carriers with germline + somatic BRCA2 or somatic BRCA1/2 mutations demonstrated a significant protective effect on OS (Fig. 3 A). The hazard ratio of germline + somatic BRCA2 was 0.27 (95% CI: 0.08–0.85, p-value: 0.026), and for somatic BRCA1/2 , it was 0.30 (95% CI: 0.09–0.96, p-value: 0.042). Carriers with germline + somatic ATM exhibited a protective effect on PFS, with a hazard ratio of 0.54 (95% CI: 0.030-1.00, p-value: 0.049), while CDH1 and STK11 showed a hazard effect on PFS (Fig. 3 B). The hazard ratio of CDH1 was 3.53 (95% CI: 1.42–8.77, p-value: 0.007), and for STK11 , it was 3.11 (95% CI: 1.17–8.22, p-value: 0.022). Additionally, it can be observed that germline + somatic mutation carriers of HR-related genes without BRCA1/2 in the VUS + group displayed a narrower 95% CI range compared to the LP + group in terms of overall survival (Fig. 3 A; 95% CI: 0.30–1.02 VS. 0.25–1.69, p-value: 0.057 VS. 0.372) and progression-free survival (Fig. 3 B; 95% CI: 0.42–0.89 VS. 0.33–1.21, p-value: 0.011 VS. 0.165). BRCAness mutation and Drug sensitivity We assessed the response rates of patients who underwent platinum-based chemotherapy, comparing mutation carriers to non-carriers. Two patients without information on drug response were excluded from the analysis. Out of the 227 patients included, 190 showed sensitivity to platinum-based chemotherapy, while 37 exhibited resistance or refractory response. Under the LP + grouping strategy, carriers of germline pathogenic variants in HR-related genes demonstrated a significant association with drug response (p-value: 0.029). However, the somatic status of these genes alone did not show a correlation with chemotherapy response. Nevertheless, when germline and somatic pathogenic variants were combined, we observed a significant association between deleterious mutations in BRCA1/2 and HR-related genes and a better treatment response (p-values: 0.015 and 0.004, respectively) (Table 2 ). Table 2 Effects of different classification of BRCA1/2 and all HR genes mutation on chemotherapy response. Genes Chemosensitivity p-value Chemosensitivity p-value Sensitive, N = 190 n (%) Non-sensitive †, N = 37 n (%) Sensitive, N = 190 n (%) Non-sensitive, N = 37 n (%) Germline LP+ VUS+ BRCA1 38 (20.0) 3 (8.1) 0.137 47 (24.7) 3 (8.1) 0.044 BRCA2 8 (4.2) 0 (0.0) 0.433 18 (9.5) 0 (0.0) 0.106 BRCA1/2 45 (23.7) 3 (8.1) 0.057 61 (32.1) 3 (8.1) 0.006 HRo 6 (3.2) 0 (0.0) 0.593 40 (21.1) 9 (24.3) 0.823 HR 50 (26.3) 3 (8.1) 0.029 90 (47.4) 12 (32.4) 0.136 non-HR 0 (0.0) 1 (2.7) 0.163 30 (15.8) 9 (24.3) 0.307 Somatic BRCA1 12 (6.3) 1 (2.7) 0.632 13 (6.8) 1 (2.7) 0.559 BRCA2 6 (3.2) 0 (0.0) 0.593 10 (5.3) 0 (0.0) 0.322 BRCA1/2 17 (8.9) 1 (2.7) 0.340 21 (11.1) 1 (2.7) 0.205 HRo 15 (7.9) 1 (2.7) 0.437 23 (12.1) 1 (2.7) 0.159 HR 30 (15.8) 2 (5.4) 0.161 40 (21.1) 2 (5.4) 0.044 non-HR 131 (68.9) 23 (62.2) 0.538 131 (68.9) 24 (64.9) 0.768 Somatic + Germline BRCA1 50 (26.3) 4 (10.8) 0.069 60 (31.6) 4 (10.8) 0.018 BRCA2 14 (7.4) 0 (0.0) 0.183 28 (14.7) 0 (0.0) 0.026 BRCA1/2 61 (32.1) 4 (10.8) 0.015 80 (42.1) 4 (10.8) 0.001 HRo 20 (10.5) 1 (2.7) 0.233 56 (29.5) 10 (27.0) 0.919 HR 76 (40.0) 5 (13.5) 0.004 116 (61.1) 13 (35.1) 0.006 non-HR 131 (68.9) 23 (62.2) 0.538 141 (74.2) 28 (75.7) 1.000 †Non-sensitive means patients with platinum-resistant or -refractory EOC. In the VUS + classification, germline carriers of BRCA1 and BRCA1/2 , as well as germline + somatic carriers of BRCA1, BRCA2 , and BRCA1/2 mutations, showed a significant correlation with a better treatment response (p-values: 0.044 and 0.006 for germline mutations, 0.018, 0.026, and 0.001 for germline and somatic mutations). Notably, within the VUS + grouping, 20 carriers of BRCA1/2 VUS were sensitive to platinum-based chemotherapy, while none of the VUS carriers exhibited resistance. HR-related somatic and germline + somatic carriers also exhibited a significant association with a better response (p-value: 0.044 for somatic mutation, 0.006 for germline and somatic variants). In this context, the VUS + classification identified 42 HR-related VUS carriers who showed sensitivity to platinum-based chemotherapy, while introducing 8 carriers who exhibited resistance (Table 2 ). We further conducted a similar analysis among patients who received treatment with the PARP inhibitor Niraparib, leading to notable observations. Within the LP + classification, individuals harboring germline and somatic pathogenic mutations in BRCA1, BRCA1/2 , and HR genes demonstrated a pronounced increase in sensitivity to Niraparib (p-values: 0.008, 0.008, and 0.040, respectively). However, among the 25 patients included in our study cohort, only one carrier exhibited a pathogenic mutation in other HR-related genes, and no carriers with pathogenic BRCA2 variants were identified. As a result, the sensitivity rate among carriers of BRCA2 gene mutations did not reach statistical significance. Similarly, within the VUS + classification, a significant association between BRCA1, BRCA1/2 mutations, and drug sensitivity was observed (p-values: 0.040, 0.041) ( Supplementary Table 5 ). DISCUSSION The landscape of ovarian cancer in our cohort differs from that reported in the TCGA cohort. One significant reason for this discrepancy is the variation in histological types between the two cohorts. While all samples in the TCGA cohort in report were of high-grade serous ovarian cancer (HGSOC), our cohort comprised various histological types, with HGSOC accounting for 84.7% of cases. Notably, non-HGSOC samples exhibited a distinct mutation landscape, particularly in the PIK3CA gene, where 67% of mutations occurred in non-HGSOC cases compared to 33% in HGSOC. Additionally, non-HGSOC samples displayed a relatively lower frequency of TP53 mutations. The distribution of BRCA1/2 mutations varied across different clinical subgroups within our cohort ( Supplementary Tables 6 and 7 ), which included multiple histological types of ovarian cancer. Consistent with previous studies, the prevalence of germline BRCA1/2 mutations ranged from 16.7–28.5%, while somatic mutations ranged from 4.1–8.7% [ 20 , 28 – 31 , 41 ]. Our data (20.4% germline, 7.8% somatic) falls within this range. The variation in overall mutation rates across studies can be attributed to the different histological types included in each study [ 22 , 42 , 43 ], as well as discrepancies in variant interpretation among laboratories [ 44 , 45 ]. Comparing the rates of mutations in HR genes is challenging as well, as there is inconsistency in the gene lists associated with HR-related mutations. In our study, we observed that BRCA1/2 germline + somatic mutation carriers exhibited an extended OS and HR germline + somatic mutation carriers showed prolonged OS and PFS. Combining germline and somatic mutation information demonstrated improved predictive power compared to using germline or somatic mutations alone. HR-related mutations showed similar or even superior predictive ability compared to BRCA1/2 mutations. Mutations have better protective or worse hazard effect under VUS + grouping than LP + grouping. However, it is important to note that the relationship between BRCA1/2 mutations and survival outcomes in ovarian cancer is complex. Studies have reported that BRCA1/2 mutation carriers exhibit longer progression-free survival (PFS) [ 46 ], or improved overall survival (OS) [ 20 ], or both. A meta-analysis of 23 studies indicated that BRCA1 mutations are associated with improved OS but not PFS, while BRCA2 mutations do not significantly impact OS or PFS [ 47 ]. Another study conducted in Korea found no difference in OS or PFS between BRCA1 mutation carriers and non-carriers, while BRCA2 mutation carriers had longer PFS [ 33 ]. Factors such as histological type, treatment protocols, and variant interpretation, which were not consistently reported in some studies, can significantly influence survival predictions. A key aspect of our study is the inclusion of VUS. According to the American College of Medical Genetics and Genomics (ACMG) [ 48 ], VUS refers to variants with a 6%-95% likelihood of being harmful. Previous studies treated VUS carriers similarly to carriers of benign variants. However, our results demonstrate that VUS in BRCA1/2 play a significant role in prognosis and the prediction of platinum-based drug sensitivity. This discrepancy can be attributed to the advancements made in the interpretation of BRCA1/2 variants in recent years. Inter-laboratory comparison studies conducted in 2016 revealed a 5% discrepancy in interpretation for all BRCA1/2 mutations [ 45 ], whereas a 2020 interpretation comparison in China demonstrated an interpretation accuracy of 99.97% for leading laboratories [ 49 ]. The prognostic significance of BRCA mutations in platinum-based therapy has been reported in several clinical trials [ 20 ]. Our data corroborates the effects of these mutations in a real-world setting. While the presence of somatic BRCA1/2 mutations alone did not reach statistical significance in predicting chemotherapy response, considering both germline and somatic mutations together demonstrated superior performance. Mutations in HR-related genes also served as predictive markers in chemotherapy. Although they have been reported as prognostic markers in PARP inhibitor treatment, we lacked sufficient carriers in our dataset for validation. CONCLUSIONS In conclusion, we observed that carriers of HR-related gene mutations exhibited longer OS and PFS compared to non-carriers. Specifically, BRCA1/2 mutation carriers showed prolonged OS compared to non-carriers. Notably, BRCA2 mutation carriers had longer OS only when variants of uncertain significance (VUS) were taken into consideration. Furthermore, the combination of germline and somatic variants of BRCA1, BRCA1/2 , and other HR-related genes significantly improved the prediction ability for prognosis and drug sensitivity in chemotherapy. The presence of VUS in BRCA1/2 gene influenced both survival prediction and chemotherapy sensitivity. Importantly, considering both germline and somatic variants together enhanced the prediction ability for chemotherapy response and PARP inhibitor therapy. Declarations Disclosure All authors declare that they have no conflicts of interest to disclose. Contributors of the authors LL, KS and MW conceived of the original idea for the study, interpreted results, carried out the statistical analysis, edited the paper and was overall guarantor. LL and JZ obtained ethical approval, contributed to the preparation of the data set, interpreted results and contributed to drafts of the paper. NS, BS, DZ, LL, YG, KW, QL, CL, HC, BC, LW, KS and JL contributed to the study design, interpretation of results and commented on drafts of the paper. Specially, JL and MW from Peking Union Medical College Hospital, NS and YG from Peking University Cancer Hospital & Institute, DZ and QL from Shandong Cancer Hospital and Institute, and YL and QL Peking University devoted their leadership and professional clinical care in this study. YY and HW conducted the pathological evaluation and reviewed the original materials. All authors have approved the final version of the manuscript. Acknowledgements We thank Ms. Yingqi Wang, Ms. Meng Liu, Ms. Shujiao Mu, Ms. Lvzhi Ren, Ms. Yilu Liu, Ms. Rui Wang and Dr. Ke Ma, Dr. Changbin Zhu and Dr Di Shao from BGI Genomics. Their diligent and generous help enabled the smooth progression of this project. Last and most important, we always devote our thanks to our patients and friends. Funding This study is supportedby the State Key Laboratory for Complex, Severe and Rare Diseases in Peking Union Medical College Hospital, by the Key Research Project of Beijing Natural Science Foundation (No. Z220013), by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2024-I2M-C&T-B-029), by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-083, 2022-PUMCH-C-010, 2022-PUMCH-C-022 and 2022-PUMCH-D-003), and by Peking Union Medical College Hospital Young Reserve Talent Development Program (No. UHB12577). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ethics approval and registration The Institutional Review Board of Peking Union Medical College Hospital approved this study (No. HS-1245 and No. HS-1474). The registration numbers are NCT03015376 and NCT03294343 ( clinicaltrials.gov, registered on January 10, 2017 and on September 27, 2017, respectively). The data the first patient was enrolled was February 24, 2017. The Chinese Human Genetic Resources Management Office of the National Ministry of Science and Technology approved this study (registration No.: [2017] 1901, http://www.most.gov.cn/bszn/new/rlyc/jgcx/index.htm). Statement of submission The paper is not under consideration by another journal, and the results presented in this work have not been previously presented or published. Consent for publication Consents for publication have been obtained from all patients. Availability of data and material All data of this study has been contained in the supplementary files. References Sung, H., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA Cancer J Clin, 2021. 71(3): p. 209–249. Xia, C., et al., Cancer statistics in China and United States, 2022: profiles, trends, and determinants . Chin Med J (Engl), 2022. 135(5): p. 584–590. 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Version 1.2020 - March 11 , 2020. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf . Finch, A., et al., Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation . JAMA, 2006. 296(2): p. 185–92. Dougherty, B.A., et al., Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting . Oncotarget, 2017. 8(27): p. 43653–43661. Yang, D., et al., Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer . JAMA, 2011. 306(14): p. 1557–65. Bolton, K.L., et al., Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer . JAMA, 2012. 307(4): p. 382–90. Pennington, K.P., et al., Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas . Clin Cancer Res, 2014. 20(3): p. 764–75. Coleman, R.L., et al., Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer . N Engl J Med, 2019. 381(25): p. 2403–2415. Enomoto, T., et al., The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE) . Int J Gynecol Cancer, 2019. 29(6): p. 1043–1049. Gonzalez-Martin, A., et al., Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer . N Engl J Med, 2019. 381(25): p. 2391–2402. Yao, Q., et al., Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics . Front Oncol, 2022. 12: p. 709645. Norquist, B.M., et al., Inherited Mutations in Women With Ovarian Carcinoma . JAMA Oncol, 2016. 2(4): p. 482–90. Yost, S., et al., Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers . JNCI Cancer Spectr, 2019. 3(2): p. pkz028. Li, A., et al., BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls . Gynecol Oncol, 2018. 151(1): p. 145–152. Shi, T., et al., BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer . Int J Cancer, 2017. 140(9): p. 2051–2059. Wu, X., et al., The First Nationwide Multicenter Prevalence Study of Germline BRCA1 and BRCA2 Mutations in Chinese Ovarian Cancer Patients . Int J Gynecol Cancer, 2017. 27(8): p. 1650–1657. You, Y., et al., Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer . Front Oncol, 2020. 10: p. 295. Chao, A., et al., Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer . Oncotarget, 2016. 7(51): p. 85529–85541. Eoh, K.J., et al., Comparison of Clinical Outcomes of BRCA1/2 Pathologic Mutation, Variants of Unknown Significance, or Wild Type Epithelial Ovarian Cancer Patients . Cancer Res Treat, 2017. 49(2): p. 408–415. Seo, J.H., et al., Prevalence and oncologic outcomes of BRCA1/2 mutation and variant of unknown significance in epithelial ovarian carcinoma patients in Korea . Obstet Gynecol Sci, 2019. 62(6): p. 411–419. Berger, A.C., et al., A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers . Cancer Cell, 2018. 33(4): p. 690–705 e9. Integrated genomic analyses of ovarian carcinoma . Nature, 2011. 474(7353): p. 609–15. Ding, L., et al., Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics . Cell, 2018. 173(2): p. 305–320 e10. Li, W., L. Li, and M. Wu, A family pedigree of malignancies associated with BRCA1 pathogenic variants: a reflection of the state of art in China . Hered Cancer Clin Pract, 2019. 17: p. 26. Li, L., L. Qiu, and M. Wu, A survey of willingness about genetic counseling and tests in patients of epithelial ovarian cancer . Zhonghua Yi Xue Za Zhi, 2017. 97(43): p. 3412–3415. Lee, Y., et al., Advances in the recognition of tubal intraepithelial carcinoma: applications to cancer screening and the pathogenesis of ovarian cancer . Adv Anat Pathol, 2006. 13(1): p. 1–7. Cheng, A., et al., Pathological findings following risk-reducing salpingo-oophorectomy in BRCA mutation carriers: A systematic review and meta-analysis . Eur J Surg Oncol, 2020. 46(1): p. 139–147. Bu, H., et al., BRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group . J Obstet Gynaecol Res, 2019. 45(11): p. 2267–2274. Witjes, V.M., et al., Probability of detecting germline BRCA1/2 pathogenic variants in histological subtypes of ovarian carcinoma. A meta-analysis . Gynecol Oncol, 2022. 164(1): p. 221–230. Sugino, K., et al., Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients . Sci Rep, 2019. 9(1): p. 17808. Eggington, J.M., et al., A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes . Clin Genet, 2014. 86(3): p. 229–37. Amendola, L.M., et al., Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium . Am J Hum Genet, 2016. 98(6): p. 1067–1076. Kim, S.I., et al., Effect of BRCA mutational status on survival outcome in advanced-stage high-grade serous ovarian cancer . J Ovarian Res, 2019. 12(1): p. 40. Huang, Y.W., Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis . Medicine (Baltimore), 2018. 97(2): p. e9380. Nykamp, K., et al., Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria . Genet Med, 2017. 19(10): p. 1105–1117. Shao, K., et al., Comprehensive evaluation of BRCA1/2 variant interpretation ability among laboratories in China . J Med Genet, 2022. 59(3): p. 230–236. Supplementary Material Supplementary Figures and Supplementary Table are not available with this version. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 13 Aug, 2025 Read the published version in npj Precision Oncology → Version 1 posted Editorial decision: Revision requested 07 Jun, 2025 Reviews received at journal 23 May, 2025 Reviews received at journal 19 May, 2025 Reviewers agreed at journal 12 May, 2025 Reviewers agreed at journal 07 May, 2025 Reviewers agreed at journal 06 May, 2025 Reviewers invited by journal 06 May, 2025 Editor assigned by journal 30 Apr, 2025 Submission checks completed at journal 22 Apr, 2025 First submitted to journal 21 Apr, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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07:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6493572/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6493572/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41698-025-01074-6","type":"published","date":"2025-08-13T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82885090,"identity":"11e9361c-4cea-4594-a148-08e7b82a3eb2","added_by":"auto","created_at":"2025-05-16 11:45:26","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152171,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDeleterious variant type and frequency in EOC patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eDistribution of pathogenicity of germline mutation carriers \u003cstrong\u003e(B) \u003c/strong\u003eDistribution of genes with germline deleterious mutations. \u003cstrong\u003e(C) \u003c/strong\u003eDistribution of mutation types of \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e. \u003cstrong\u003e(D)\u003c/strong\u003e Distribution of pathogenicity of somatic mutation carriers.\u003cstrong\u003e (E) \u003c/strong\u003eDistribution of genes with deleterious somatic mutations.\u003cstrong\u003e(F)\u003c/strong\u003eDistribution of mutation types of \u003cem\u003eTP53\u003c/em\u003e and \u003cem\u003eBRCA1.\u003c/em\u003e\u003cstrong\u003e (G) \u003c/strong\u003eproportion of germline, somatic, and germline + somatic mutation carriers in genes, HRo refers to HR-related genes other than \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6493572/v1/681abff78eea61f358ac75b0.jpeg"},{"id":82885089,"identity":"a34ab34f-289d-4cf5-9d55-6a4da1ed5616","added_by":"auto","created_at":"2025-05-16 11:45:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120710,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOS and PFS by mutation status.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive-year Kaplan‒Meier curve for OS and PFS in EOC patients stratified by \u003cstrong\u003e(A, D) \u003c/strong\u003egermline+somatic HR genes under LP+ strategy, \u003cstrong\u003e(B, E) \u003c/strong\u003egermline+somatic HR genes under VUS+ strategy\u003cem\u003e,(C) \u003c/em\u003egermline+somatic\u003cem\u003eBRCA1/2 \u003c/em\u003eunder VUS+ strategy\u003cem\u003e, \u003c/em\u003eand \u003cstrong\u003e(C, F)\u003c/strong\u003e.\u003cstrong\u003e \u003c/strong\u003eThe p values were calculated with the log-rank test. WT, wild-type (including no variants, benign and likely benign variants); LP+, likely pathogenic and pathogenic variants. VUS+, LP+ and VUS variants. Tier II+, class I and II somatic variants, Tier III+, class I, II and III somatic variants.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6493572/v1/6c1fa72816ab974e54aa62df.jpeg"},{"id":82885092,"identity":"4b9d5b9a-1c8e-4dd6-8367-53889a6d6037","added_by":"auto","created_at":"2025-05-16 11:45:26","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1428311,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of multivariate Cox regression with \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eBRCA1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e, \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eBRCA2\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e, and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eBRCA1/2\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e mutation status.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main effects are shown as hazard ratios with 95% confidence intervals. CI, confidence interval. *** p \u0026lt; 0.001; * 0.01 \u0026lt; p \u0026lt; 0.05; † p \u0026lt; 0.1.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6493572/v1/25244c7ac5585bdbe741dd23.jpeg"},{"id":89310654,"identity":"8e4dfdd9-2cec-4c94-9c68-425174d9889f","added_by":"auto","created_at":"2025-08-18 16:09:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3016399,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6493572/v1/f48e0cf8-365d-4e98-96d7-72c69f470508.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multigene germline and somatic testing for epithelial ovarian cancer in China","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eOvarian cancer (OC) is one of the leading causes of female cancer worldwide. According to GLOBOCAN 2020 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], there were 313,959 new cases and 207,252 deaths globally. In China, the incidence of OC has shown a stable increase from approximately 52,100 cases in 2015 to 57,090 cases in 2022, with an alarming rise in death cases from about 22,500 in 2015 to 39,306 in 2022 [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. OC exhibits the highest mortality rate among female cancers, with a five-year survival rate of only 38.9% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEpithelial ovarian cancer (EOC) represents the majority (approximately 60%) of OC cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], with about 22\u0026ndash;25% of EOC attributed to the inheritance of germline mutations in cancer predisposing genes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Ovarian cancer predisposing genes include \u003cem\u003eBRCA1\u003c/em\u003e, \u003cem\u003eBRCA2\u003c/em\u003e, other homologous recombination repair (HR) genes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], mismatch repair (MMR) genes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and ovarian cancer-related tumor suppressor genes such as TP53 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Guidelines from the National Comprehensive Cancer Network (NCCN) emphasize the importance of screening high-risk populations for OC and BC predisposition genes, as this provides carriers with opportunities to reduce their OC and BC risks [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Individuals carrying \u003cem\u003eBRCA1/2\u003c/em\u003e and other high or moderate penetrance genes, should consider clinical interventions such as regular physical examinations, mammograms or MRI scans, and risk-reducing surgeries such as risk-reducing salpingo-oophorectomy (RRSO) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, patients with ovarian cancer who carry \u003cem\u003eBRCA1/2\u003c/em\u003e or other HR-related genes can potentially benefit from platinum-based agents and PARP inhibitors based on genetic testing results [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. \u003cem\u003eBRCA1/2\u003c/em\u003e genes have also demonstrated value in prognosis prediction, as several studies suggest that \u003cem\u003eBRCA1/2\u003c/em\u003e carriers may experience longer survival times [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is a considerable diversity of mutations in \u003cem\u003eBRCA1\u003c/em\u003e, \u003cem\u003eBRCA2\u003c/em\u003e, and other genes observed in different populations, indicating the need for comprehensive studies worldwide [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. While germline mutation spectrum studies have been conducted in Chinese populations, the mutation spectrum in Chinese populations differs from that of Western populations [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In contrast, there are relatively few reports on the somatic mutation spectrum [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince deleterious mutations often indicate pathogenic or likely pathogenic alterations, variants of uncertain significance, which are less harmful, have received less attention [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. There remains a lack of systematic evaluation regarding the overall impact of all HR-related gene mutations on drug sensitivity and prognosis in EOC patients.\u003c/p\u003e \u003cp\u003eIn this study, we present a comprehensive analysis of the germline and somatic mutation spectra in HR-related genes in Chinese ovarian cancer patients. Our primary objective is to explore the correlations between these mutations, drug sensitivity, and prognosis, thereby shedding light on potential implications for clinical management and treatment strategies.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval and patient recruitment\u003c/h2\u003e \u003cp\u003e Prior to participation, all patients provided informed consent after being fully informed about the study. The study was conducted in accordance with ethical principles and guidelines. A total of 1411 ovarian cancer patients were recruited for this study during February 24, 2017 and December 31, 2018. After excluding 1182 patients based on our criteria, a total of 229 patients were included for analysis. (\u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e). These patients received standard treatment and underwent genetic testing. Clinical information, including age, pathological subtype, stage, tumor size and site, and family history, was collected for analysis. (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cb\u003eTreatment and pathological evaluation.\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePatients were diagnosed with epithelial ovarian cancer (EOC) through core needle biopsy, laparoscopic biopsy, or debulking surgeries. Debulking surgeries, consisting of primary or interval surgeries combined with platinum-based chemotherapy, were performed following established guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Sensitivity to platinum-based chemotherapy was determined based on the following criteria: sensitive or resistant, indicating recurrence beyond or within 6 months after the completion of standard chemotherapy, respectively; refractory, indicating recurrence within 4 weeks after the completion of standard chemotherapy or disease progression during the chemotherapy duration. Follow-up was conducted until June 1, 2022, with recurrence and/or progression defined as the appearance of new lesions confirmed by imaging evaluation or histology, or increased tumor markers as identified by physicians. Mortality information was obtained from case reports and/or death certificates.\u003c/p\u003e \u003cp\u003eA centralized pathological evaluation was conducted by two independent pathologists to ensure consistency in the assessment of histological subtypes and modification of International Federation of Gynecology and Obstetrics (FIGO) stages. The analysis of drug sensitivity and survival outcomes specifically focused on high-grade serous carcinoma (HGSC) and clear cell/endometrioid subtypes, as different histological types are characterized by distinct mutational spectra [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample preparation and sequencing\u003c/h3\u003e\n\u003cp\u003eDNA extraction from ovarian cancer tissue and blood samples of patients was performed using the Qiagen DNA Mini Kit (Qiagen, Hilden, Germany). The DNA quantity and integrity were assessed using the Qubit Fluorometer (Life Technologies). Qualified DNA samples were subjected to capture-based targeted sequencing using the QseqT ovarian cancer panel (21 genes) or the OseqT pan-cancer panel (508 genes), followed by library construction for the BGISEQ-500 platform. Each sample generated sequencing data with an average sequencing depth of over 500x and target region coverage exceeding 99%.\u003c/p\u003e \u003cp\u003e \u003cb\u003eVariants calling and data interpretation.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe sequencing reads were filtered using SOAPnuke 1.5 and aligned to the hg19 reference genome using BWA 0.7.12. Germline and somatic variants were called using GATK 3.4 following the GATK best practice. Single nucleotide variants (SNVs) were called using GATK Unified Genotyper, while indels were called using GATK Haplotype. All variants were filtered based on quality depth, mapping quality, strand bias, and read position.\u003c/p\u003e\n\u003ch3\u003eVariant classification\u003c/h3\u003e\n\u003cp\u003eVariants were annotated using ANNOVAR. The focus of variant interpretation was on 21 genes, including 11 homologous recombination repair (HR) related genes (\u003cem\u003eATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD50\u003c/em\u003e, and \u003cem\u003eRAD51C\u003c/em\u003e), 5 mismatch repair related genes (\u003cem\u003eMLH1, MSH2, MSH6, PMS1\u003c/em\u003e, and \u003cem\u003ePMS2\u003c/em\u003e), and 5 ovarian cancer related genes (\u003cem\u003eCDH1, MUTYH, PTEN, STK11\u003c/em\u003e, and \u003cem\u003eTP53\u003c/em\u003e). Germline variants were classified into five categories according to the recommendations of the American College of Medical Genetics (ACMG): pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). Somatic variants were classified into four categories following the guidelines of the Association for Molecular Pathology (AMP): tier I (variants with strong clinical significance), tier II (variants with potential clinical significance), tier III (variants of unknown clinical significance), and tier IV (variants deemed benign or likely benign). To ensure consistency between germline and somatic variants, tier I, tier II, and tier III were considered equivalent to P, LP, and VUS, respectively, while tier IV corresponded to B and LB. Variants classified as P or LP were confirmed using quantitative polymerase chain reaction (qPCR) or Sanger sequencing. The interpretation of certain variants was updated in 2022 based on updated literature evidence. Variant details are included in \u003cb\u003eSupplementary Tables\u0026nbsp;2 and 3\u003c/b\u003e.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using R 3.5.1. The significance of the association between mutation prevalence and clinical characteristics was assessed using an appropriate method (Chi-square test or Fisher exact test) based on the number of cases. Survival curves were plotted according to the Kaplan-Meier method and compared by the log-rank test. Multivariable analysis of progression-free survival and overall survival was conducted using the Cox regression model.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment and clinical information\u003c/h2\u003e \u003cp\u003eA total of 229 ovarian cancer patients were recruited for this study, all of whom underwent panel sequencing of 21 genes. Among them, 141 patients also received panel sequencing of 508 cancer-related genes.\u003c/p\u003e \u003cp\u003eThe median age of the patients was 55, ranging from 24 to 62 years. The majority of patients (194, 84.7%) had the pathological subtype of High-grade serous ovarian cancer (HGSOC), while the remaining subtypes included Clear Cell Carcinoma (CCC), Endometrioid Carcinoma (EC), Low-grade serous ovarian cancer (LGSOC), Mucinous Carcinoma (MC), SCC, mixed carcinoma, and unspecific carcinoma. Approximately 21% (48/229) of the patients were in the early stage (I or II), while 79% (181/229) were in the late stage (III or IV). It is worth noting that 42.4% (97/229) of the patients had a family history of cancer. All patients received chemotherapy, and 26 of them also received additional PARP inhibitor treatment (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eClinicopathological characteristics of the EOC patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e508 genes panel cohort (N\u0026thinsp;=\u0026thinsp;141)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 genes panel cohort (N\u0026thinsp;=\u0026thinsp;229)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (IQR), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54.0 (48.0, 62.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55.0 (48.0, 62.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistribution, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42 (29.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72 (31.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99 (70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e157 (68.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e125 (88.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e200 (87.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHGSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e122 (86.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e194 (84.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLGSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrioid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (3.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIGO stage, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (9.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27 (11.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90 (63.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e148 (64.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33 (14.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer site, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e128 (90.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e214 (93.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFallopian tube\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease status at panel testing, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126 (89.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e201 (87.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (12.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse to platinum-based chemotherapy, no./total no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117/139 (84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e190/227 (83.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResistant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20/139 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30/227 (13.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefractory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/139 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7/227 (3.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial chemotherapy with bevacizumab - Yes, no./total no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13/74 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17/138 (12.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePARPi therapy - Yes, no./total no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21/124 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26/207 (12.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePFS status - Recurrence/Progression, no./total no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e107/140 (76.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e183/228 (80.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS status - Death, no./total no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46/140 (32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83/228 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersonal history of cancer - Yes, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (6.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersonal history of breast cancer - Yes, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of cancer - Yes, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60 (42.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97 (42.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of cancer for HBOC testing - Yes, no. (%)\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (8.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: EOC, epithelial ovarian cancer; IQR, interquartile range; HGSC/LGSC, high/low-grade serous carcinoma; FIGO, International Federation of Gynecology and Obstetrics; PFS, progression-free survival; OS, overall survival; HBOC, hereditary breast and ovarian cancer.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u0026dagger;Other EOC histological subtypes include mixed carcinoma (508: n\u0026thinsp;=\u0026thinsp;2, 21: n\u0026thinsp;=\u0026thinsp;3), squamous carcinoma (21: n\u0026thinsp;=\u0026thinsp;1), carcinosarcoma (508: n\u0026thinsp;=\u0026thinsp;2, 21: n\u0026thinsp;=\u0026thinsp;2).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u0026Dagger;Family history of cancer for HBOC testing criteria was according to NCCN Guidelines for \u0026ldquo;Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 1.2015\u0026rdquo;.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSomatic Mutation landscape in 141 patients\u003c/h3\u003e\n\u003cp\u003eSomatic single nucleotide variants (SNVs) and insertions/deletions (Indels) were detected through panel sequencing of both the 21 genes and the 508 genes panel. Among the 141 patients who underwent Oseq-T pan-cancer panel sequencing, TP53 mutations were observed in 72% of patients, followed by \u003cem\u003eBRCA1\u003c/em\u003e mutations in 11% of patients, \u003cem\u003eBRCA2\u003c/em\u003e mutations in 6% of patients, and \u003cem\u003ePIK3CA\u003c/em\u003e mutations in 10% of patients \u003cb\u003e(Supplementary Fig.\u0026nbsp;2A)\u003c/b\u003e. Within the \u003cem\u003ePIK3CA\u003c/em\u003e mutations, specific mutations such as p.E542K, p.E545K, and p.H1047R were detected in 2, 2, and 3 patients, respectively \u003cb\u003e(Supplementary Fig.\u0026nbsp;2B)\u003c/b\u003e. Additionally, mutations in \u003cem\u003eARID1A\u003c/em\u003e (7% of patients), and \u003cem\u003eNF1\u003c/em\u003e (5% of patients) were also identified.\u003c/p\u003e \u003cp\u003eIn our cohort of 229 patients, a significant proportion (23.6%, 54/229) exhibited the presence of germline pathogenic or likely pathogenic variants in 21 genes, while 29.7% (68/229) carried variants of uncertain significance (VUS). Specifically, 17.9% of patients carried \u003cem\u003eBRCA1\u003c/em\u003e mutations, 3.5% carried \u003cem\u003eBRCA2\u003c/em\u003e mutations, and 23.1% carried mutations in HR-related genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, G). Among these genes, a total of 56 mutations were identified, with \u003cem\u003eBRCA1\u003c/em\u003e (73.2%, 41), \u003cem\u003eBRCA2\u003c/em\u003e (14.3%, 8), and \u003cem\u003ePALB2\u003c/em\u003e (3.6%, 2) being the most prevalent (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Furthermore, 98.2% (55/56) of the mutations were harbored in homologous recombination repair (HR) genes, while 1.8% (1/56) occurred in \u003cem\u003eSTK11\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The main mutation types observed in \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e were both frameshift mutations (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eRegarding somatic mutations, 66.4% of patients carried pathogenic or likely pathogenic level mutations (Tier I and II). Among the 207 somatic mutations identified, 73.9% (153) were deleterious mutations in \u003cem\u003eTP53\u003c/em\u003e, 6.3% (13) in \u003cem\u003eBRCA1\u003c/em\u003e, and 3.4% (7) in \u003cem\u003eBRCA2\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Additionally, 8.7% (18) of the deleterious mutations were found in other HR-related genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). The main mutation type observed in \u003cem\u003eTP53\u003c/em\u003e was missense mutations (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003eBy considering both germline and somatic pathogenic or likely pathogenic variants, the carrier rates of deleterious \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e mutations increased to 23.6% and 6.1%, respectively. Moreover, 35.4% of patients carried at least one germline/somatic deleterious variants in HR-related genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG).\u003c/p\u003e\n\u003ch3\u003eOvarian cancer Susceptibility Gene and Prognosis\u003c/h3\u003e\n\u003cp\u003eTo assess the clinical significance of variants of uncertain significance (VUS), we implemented two distinct classification strategies. The initial approach, referred to as \"LP+\" classification, involved categorizing carriers with germline pathogenic or likely pathogenic variants and somatic Tier I/II variants as having deleterious mutations, while the remaining patients were classified as non-pathogenic. The second strategy, known as \"VUS+\" classification, expanded upon the LP\u0026thinsp;+\u0026thinsp;classification by including germline VUS and somatic Tier III variants as additional deleterious mutations. Carriers were assigned to the mutation group (Mut, means VUS+/Tier III+), while non-carriers were classified as the wildtype group (WT).\u003c/p\u003e \u003cp\u003eSurvival analyses were conducted to compare the outcomes of carriers with germline, somatic, and germline\u0026thinsp;+\u0026thinsp;somatic variants using the LP+/VUS\u0026thinsp;+\u0026thinsp;strategy. Only 200 patients were included in survival analysis (\u003cb\u003eSupplementary Table\u0026nbsp;4\u003c/b\u003e). Univariate analysis revealed that under the LP\u0026thinsp;+\u0026thinsp;grouping strategy, patients with deleterious mutations in \u003cem\u003eBRCA1/2\u003c/em\u003e and HR-related genes (somatic\u0026thinsp;+\u0026thinsp;germline) exhibited prolonged overall survival (OS) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA for HR, \u003cb\u003eSupplementary Fig.\u0026nbsp;3A\u003c/b\u003e for \u003cem\u003eBRCA1/2\u003c/em\u003e, p-value: 0.016, 0.027), and a similar but non-significant trend was observed in progression-free survival (PFS) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD for HR, \u003cb\u003eSupplementary Fig.\u0026nbsp;3B\u003c/b\u003e for \u003cem\u003eBRCA1/2\u003c/em\u003e, p-value: 0.071, 0.16) compared to non-carriers. In the VUS\u0026thinsp;+\u0026thinsp;grouping strategy, carriers of HR related genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), \u003cem\u003eBRCA2\u003c/em\u003e (\u003cb\u003eSupplementary Fig.\u0026nbsp;3C\u003c/b\u003e) and \u003cem\u003eBRCA1/2\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) deleterious mutations (somatic\u0026thinsp;+\u0026thinsp;germline) demonstrated extended OS (p-value: 0.002, 0.018, and 0.006, respectively) compared to non-carriers. A similar trend was observed in PFS, although the log-rank test did not reach statistical significance (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE for HR, \u003cb\u003eSupplementary Fig.\u0026nbsp;3D\u003c/b\u003e for \u003cem\u003eBRCA2\u003c/em\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF for \u003cem\u003eBRCA1/2\u003c/em\u003e, p-value: 0.099, 0.1, and 0.41, respectively). Notably, carriers of somatic \u003cem\u003eBRCA1/2\u003c/em\u003e mutations exhibited significantly longer OS than non-carriers (\u003cb\u003eSupplementary Fig.\u0026nbsp;3F, p\u003c/b\u003e-value: 0.047). However, \u003cem\u003eBRCA1\u003c/em\u003e mutations did not significantly impact survival time in terms of OS or PFS under either classification strategy.\u003c/p\u003e \u003cp\u003eSubsequently, we conducted multivariate survival analysis, adjusting for age, histology, and FIGO stage. In both the LP\u0026thinsp;+\u0026thinsp;and VUS\u0026thinsp;+\u0026thinsp;groups, carriers of germline\u0026thinsp;+\u0026thinsp;somatic HR-related mutations demonstrated prolonged OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA; LP+: p-value\u0026thinsp;=\u0026thinsp;0.005, VUS+: p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB; LP+: p-value\u0026thinsp;=\u0026thinsp;0.018, VUS+: p-value\u0026thinsp;=\u0026thinsp;0.009). Moreover, germline\u0026thinsp;+\u0026thinsp;somatic \u003cem\u003eBRCA1/2\u003c/em\u003e carriers exhibited extended OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA; LP+: p-value\u0026thinsp;=\u0026thinsp;0.011, VUS+: p-value\u0026thinsp;=\u0026thinsp;0.002). The hazard ratio of \u003cem\u003eBRCA1/2\u003c/em\u003e and HR-related mutation carriers in the VUS\u0026thinsp;+\u0026thinsp;group was lower than in the LP\u0026thinsp;+\u0026thinsp;group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For \u003cem\u003eBRCA1/2\u003c/em\u003e, the hazard ratio of OS was 0.46 (95% CI: 0.25\u0026ndash;0.84) in the LP\u0026thinsp;+\u0026thinsp;group and 0.41 (95% CI: 0.24\u0026ndash;0.72) in the VUS\u0026thinsp;+\u0026thinsp;group. For HR, the hazard ratio of OS was 0.46 (95% CI: 0.26\u0026ndash;0.79) in the LP\u0026thinsp;+\u0026thinsp;group and 0.43 (95% CI: 0.26\u0026ndash;0.70) in the VUS\u0026thinsp;+\u0026thinsp;group. The hazard ratio of PFS was 0.66 (95% CI: 0.47\u0026ndash;0.93) in the LP\u0026thinsp;+\u0026thinsp;group and 0.65 (95% CI: 0.47\u0026ndash;0.90) in the VUS\u0026thinsp;+\u0026thinsp;group.\u003c/p\u003e \u003cp\u003eNotably, only in the VUS\u0026thinsp;+\u0026thinsp;group, carriers with germline\u0026thinsp;+\u0026thinsp;somatic \u003cem\u003eBRCA2\u003c/em\u003e or somatic \u003cem\u003eBRCA1/2\u003c/em\u003e mutations demonstrated a significant protective effect on OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The hazard ratio of germline\u0026thinsp;+\u0026thinsp;somatic \u003cem\u003eBRCA2\u003c/em\u003e was 0.27 (95% CI: 0.08\u0026ndash;0.85, p-value: 0.026), and for somatic \u003cem\u003eBRCA1/2\u003c/em\u003e, it was 0.30 (95% CI: 0.09\u0026ndash;0.96, p-value: 0.042). Carriers with germline\u0026thinsp;+\u0026thinsp;somatic \u003cem\u003eATM\u003c/em\u003e exhibited a protective effect on PFS, with a hazard ratio of 0.54 (95% CI: 0.030-1.00, p-value: 0.049), while \u003cem\u003eCDH1\u003c/em\u003e and \u003cem\u003eSTK11\u003c/em\u003e showed a hazard effect on PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The hazard ratio of \u003cem\u003eCDH1\u003c/em\u003e was 3.53 (95% CI: 1.42\u0026ndash;8.77, p-value: 0.007), and for \u003cem\u003eSTK11\u003c/em\u003e, it was 3.11 (95% CI: 1.17\u0026ndash;8.22, p-value: 0.022). Additionally, it can be observed that germline\u0026thinsp;+\u0026thinsp;somatic mutation carriers of HR-related genes without \u003cem\u003eBRCA1/2\u003c/em\u003e in the VUS\u0026thinsp;+\u0026thinsp;group displayed a narrower 95% CI range compared to the LP\u0026thinsp;+\u0026thinsp;group in terms of overall survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA; 95% CI: 0.30\u0026ndash;1.02 VS. 0.25\u0026ndash;1.69, p-value: 0.057 VS. 0.372) and progression-free survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB; 95% CI: 0.42\u0026ndash;0.89 VS. 0.33\u0026ndash;1.21, p-value: 0.011 VS. 0.165).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBRCAness mutation and Drug sensitivity\u003c/h2\u003e \u003cp\u003eWe assessed the response rates of patients who underwent platinum-based chemotherapy, comparing mutation carriers to non-carriers. Two patients without information on drug response were excluded from the analysis. Out of the 227 patients included, 190 showed sensitivity to platinum-based chemotherapy, while 37 exhibited resistance or refractory response.\u003c/p\u003e \u003cp\u003eUnder the LP\u0026thinsp;+\u0026thinsp;grouping strategy, carriers of germline pathogenic variants in HR-related genes demonstrated a significant association with drug response (p-value: 0.029). However, the somatic status of these genes alone did not show a correlation with chemotherapy response. Nevertheless, when germline and somatic pathogenic variants were combined, we observed a significant association between deleterious mutations in \u003cem\u003eBRCA1/2\u003c/em\u003e and HR-related genes and a better treatment response (p-values: 0.015 and 0.004, respectively) (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\u003eEffects of different classification of BRCA1/2 and all HR genes mutation on chemotherapy response.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGenes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eChemosensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eChemosensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSensitive, N\u0026thinsp;=\u0026thinsp;190\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eNon-sensitive\u003c/b\u003e\u0026dagger;, \u003cb\u003eN\u0026thinsp;=\u0026thinsp;37\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eSensitive, N\u0026thinsp;=\u0026thinsp;190\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eNon-sensitive, N\u0026thinsp;=\u0026thinsp;37\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGermline\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eLP+\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eVUS+\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1/2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61 (32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-HR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.307\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSomatic\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.559\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.322\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1/2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-HR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e131 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (62.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e131 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (64.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSomatic\u0026thinsp;+\u0026thinsp;Germline\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60 (31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28 (14.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1/2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 (27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e116 (61.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (35.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-HR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e131 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (62.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e141 (74.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28 (75.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u0026dagger;Non-sensitive means patients with platinum-resistant or -refractory EOC.\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 the VUS\u0026thinsp;+\u0026thinsp;classification, germline carriers of \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA1/2\u003c/em\u003e, as well as germline\u0026thinsp;+\u0026thinsp;somatic carriers of \u003cem\u003eBRCA1, BRCA2\u003c/em\u003e, and \u003cem\u003eBRCA1/2\u003c/em\u003e mutations, showed a significant correlation with a better treatment response (p-values: 0.044 and 0.006 for germline mutations, 0.018, 0.026, and 0.001 for germline and somatic mutations). Notably, within the VUS\u0026thinsp;+\u0026thinsp;grouping, 20 carriers of \u003cem\u003eBRCA1/2\u003c/em\u003e VUS were sensitive to platinum-based chemotherapy, while none of the VUS carriers exhibited resistance. HR-related somatic and germline\u0026thinsp;+\u0026thinsp;somatic carriers also exhibited a significant association with a better response (p-value: 0.044 for somatic mutation, 0.006 for germline and somatic variants). In this context, the VUS\u0026thinsp;+\u0026thinsp;classification identified 42 HR-related VUS carriers who showed sensitivity to platinum-based chemotherapy, while introducing 8 carriers who exhibited resistance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe further conducted a similar analysis among patients who received treatment with the PARP inhibitor Niraparib, leading to notable observations. Within the LP\u0026thinsp;+\u0026thinsp;classification, individuals harboring germline and somatic pathogenic mutations in \u003cem\u003eBRCA1, BRCA1/2\u003c/em\u003e, and HR genes demonstrated a pronounced increase in sensitivity to Niraparib (p-values: 0.008, 0.008, and 0.040, respectively). However, among the 25 patients included in our study cohort, only one carrier exhibited a pathogenic mutation in other HR-related genes, and no carriers with pathogenic \u003cem\u003eBRCA2\u003c/em\u003e variants were identified. As a result, the sensitivity rate among carriers of \u003cem\u003eBRCA2\u003c/em\u003e gene mutations did not reach statistical significance. Similarly, within the VUS\u0026thinsp;+\u0026thinsp;classification, a significant association between \u003cem\u003eBRCA1, BRCA1/2\u003c/em\u003e mutations, and drug sensitivity was observed (p-values: 0.040, 0.041) (\u003cb\u003eSupplementary Table\u0026nbsp;5\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe landscape of ovarian cancer in our cohort differs from that reported in the TCGA cohort. One significant reason for this discrepancy is the variation in histological types between the two cohorts. While all samples in the TCGA cohort in report were of high-grade serous ovarian cancer (HGSOC), our cohort comprised various histological types, with HGSOC accounting for 84.7% of cases. Notably, non-HGSOC samples exhibited a distinct mutation landscape, particularly in the PIK3CA gene, where 67% of mutations occurred in non-HGSOC cases compared to 33% in HGSOC. Additionally, non-HGSOC samples displayed a relatively lower frequency of TP53 mutations.\u003c/p\u003e \u003cp\u003eThe distribution of \u003cem\u003eBRCA1/2\u003c/em\u003e mutations varied across different clinical subgroups within our cohort (\u003cb\u003eSupplementary Tables\u0026nbsp;6 and 7\u003c/b\u003e), which included multiple histological types of ovarian cancer. Consistent with previous studies, the prevalence of germline \u003cem\u003eBRCA1/2\u003c/em\u003e mutations ranged from 16.7\u0026ndash;28.5%, while somatic mutations ranged from 4.1\u0026ndash;8.7% [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Our data (20.4% germline, 7.8% somatic) falls within this range. The variation in overall mutation rates across studies can be attributed to the different histological types included in each study [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], as well as discrepancies in variant interpretation among laboratories [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Comparing the rates of mutations in HR genes is challenging as well, as there is inconsistency in the gene lists associated with HR-related mutations.\u003c/p\u003e \u003cp\u003eIn our study, we observed that \u003cem\u003eBRCA1/2\u003c/em\u003e germline\u0026thinsp;+\u0026thinsp;somatic mutation carriers exhibited an extended OS and HR germline\u0026thinsp;+\u0026thinsp;somatic mutation carriers showed prolonged OS and PFS. Combining germline and somatic mutation information demonstrated improved predictive power compared to using germline or somatic mutations alone. HR-related mutations showed similar or even superior predictive ability compared to \u003cem\u003eBRCA1/2\u003c/em\u003e mutations. Mutations have better protective or worse hazard effect under VUS\u0026thinsp;+\u0026thinsp;grouping than LP\u0026thinsp;+\u0026thinsp;grouping. However, it is important to note that the relationship between \u003cem\u003eBRCA1/2\u003c/em\u003e mutations and survival outcomes in ovarian cancer is complex. Studies have reported that \u003cem\u003eBRCA1/2\u003c/em\u003e mutation carriers exhibit longer progression-free survival (PFS) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], or improved overall survival (OS) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], or both. A meta-analysis of 23 studies indicated that \u003cem\u003eBRCA1\u003c/em\u003e mutations are associated with improved OS but not PFS, while \u003cem\u003eBRCA2\u003c/em\u003e mutations do not significantly impact OS or PFS [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Another study conducted in Korea found no difference in OS or PFS between \u003cem\u003eBRCA1\u003c/em\u003e mutation carriers and non-carriers, while \u003cem\u003eBRCA2\u003c/em\u003e mutation carriers had longer PFS [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Factors such as histological type, treatment protocols, and variant interpretation, which were not consistently reported in some studies, can significantly influence survival predictions.\u003c/p\u003e \u003cp\u003eA key aspect of our study is the inclusion of VUS. According to the American College of Medical Genetics and Genomics (ACMG) [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], VUS refers to variants with a 6%-95% likelihood of being harmful. Previous studies treated VUS carriers similarly to carriers of benign variants. However, our results demonstrate that VUS in \u003cem\u003eBRCA1/2\u003c/em\u003e play a significant role in prognosis and the prediction of platinum-based drug sensitivity. This discrepancy can be attributed to the advancements made in the interpretation of \u003cem\u003eBRCA1/2\u003c/em\u003e variants in recent years. Inter-laboratory comparison studies conducted in 2016 revealed a 5% discrepancy in interpretation for all \u003cem\u003eBRCA1/2\u003c/em\u003e mutations [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], whereas a 2020 interpretation comparison in China demonstrated an interpretation accuracy of 99.97% for leading laboratories [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prognostic significance of BRCA mutations in platinum-based therapy has been reported in several clinical trials [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our data corroborates the effects of these mutations in a real-world setting. While the presence of somatic \u003cem\u003eBRCA1/2\u003c/em\u003e mutations alone did not reach statistical significance in predicting chemotherapy response, considering both germline and somatic mutations together demonstrated superior performance. Mutations in HR-related genes also served as predictive markers in chemotherapy. Although they have been reported as prognostic markers in PARP inhibitor treatment, we lacked sufficient carriers in our dataset for validation.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn conclusion, we observed that carriers of HR-related gene mutations exhibited longer OS and PFS compared to non-carriers. Specifically, \u003cem\u003eBRCA1/2\u003c/em\u003e mutation carriers showed prolonged OS compared to non-carriers. Notably, \u003cem\u003eBRCA2\u003c/em\u003e mutation carriers had longer OS only when variants of uncertain significance (VUS) were taken into consideration. Furthermore, the combination of germline and somatic variants of \u003cem\u003eBRCA1, BRCA1/2\u003c/em\u003e, and other HR-related genes significantly improved the prediction ability for prognosis and drug sensitivity in chemotherapy. The presence of VUS in \u003cem\u003eBRCA1/2\u003c/em\u003e gene influenced both survival prediction and chemotherapy sensitivity. Importantly, considering both germline and somatic variants together enhanced the prediction ability for chemotherapy response and PARP inhibitor therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors of the authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLL, KS and MW conceived of the original idea for the study, interpreted results, carried out the statistical analysis, edited the paper and was overall guarantor. LL and JZ obtained ethical approval, contributed to the preparation of the data set, interpreted results and contributed to drafts of the paper. NS, BS, DZ, LL, YG, KW, QL, CL, HC, BC, LW, KS and JL contributed to the study design, interpretation of results and commented on drafts of the paper. Specially, JL and MW from Peking Union Medical College Hospital, NS and YG from Peking University Cancer Hospital \u0026amp; Institute, DZ and QL from Shandong Cancer Hospital and Institute, and YL and QL Peking University devoted their leadership and professional clinical care in this study. YY and HW conducted the pathological evaluation and reviewed the original materials. All authors have approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Ms. Yingqi Wang, Ms. Meng Liu, Ms. Shujiao Mu, Ms. Lvzhi Ren, Ms. Yilu Liu, Ms. Rui Wang and Dr. Ke Ma, Dr. Changbin Zhu and Dr Di Shao from BGI Genomics. Their diligent and generous help enabled the smooth progression of this project. Last and most important, we always devote our thanks to our patients and friends.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supportedby the State Key Laboratory for Complex, Severe and Rare Diseases in Peking Union Medical College Hospital, by the Key Research Project of Beijing Natural Science Foundation (No. Z220013), by the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2024-I2M-C\u0026amp;T-B-029), by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-083, 2022-PUMCH-C-010, 2022-PUMCH-C-022 and 2022-PUMCH-D-003), and by Peking Union Medical College Hospital Young Reserve Talent Development Program (No. UHB12577). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board of Peking Union Medical College Hospital approved this study (No. HS-1245 and No. HS-1474). The registration numbers are NCT03015376 and NCT03294343 (\u003cem\u003eclinicaltrials.gov, \u003c/em\u003eregistered on January 10, 2017 and on September 27, 2017, respectively). The data the first patient was enrolled was February 24, 2017. The Chinese Human Genetic Resources Management Office of the National Ministry of Science and Technology approved this study (registration No.: [2017] 1901, http://www.most.gov.cn/bszn/new/rlyc/jgcx/index.htm).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of submission\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe paper is not under consideration by another journal, and the results presented in this work have not been previously presented or published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsents for publication have been obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data of this study has been contained in the supplementary files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung, H., et al., \u003cem\u003eGlobal Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries\u003c/em\u003e. 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Cell, 2018. 173(2): p. 305\u0026ndash;320 e10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, W., L. Li, and M. Wu, \u003cem\u003eA family pedigree of malignancies associated with BRCA1 pathogenic variants: a reflection of the state of art in China\u003c/em\u003e. Hered Cancer Clin Pract, 2019. 17: p. 26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, L., L. Qiu, and M. Wu, \u003cem\u003eA survey of willingness about genetic counseling and tests in patients of epithelial ovarian cancer\u003c/em\u003e. Zhonghua Yi Xue Za Zhi, 2017. 97(43): p. 3412\u0026ndash;3415.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, Y., et al., \u003cem\u003eAdvances in the recognition of tubal intraepithelial carcinoma: applications to cancer screening and the pathogenesis of ovarian cancer\u003c/em\u003e. Adv Anat Pathol, 2006. 13(1): p. 1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng, A., et al., \u003cem\u003ePathological findings following risk-reducing salpingo-oophorectomy in BRCA mutation carriers: A systematic review and meta-analysis\u003c/em\u003e. Eur J Surg Oncol, 2020. 46(1): p. 139\u0026ndash;147.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBu, H., et al., \u003cem\u003eBRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group\u003c/em\u003e. J Obstet Gynaecol Res, 2019. 45(11): p. 2267\u0026ndash;2274.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitjes, V.M., et al., \u003cem\u003eProbability of detecting germline BRCA1/2 pathogenic variants in histological subtypes of ovarian carcinoma. A meta-analysis\u003c/em\u003e. Gynecol Oncol, 2022. 164(1): p. 221\u0026ndash;230.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugino, K., et al., \u003cem\u003eGermline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients\u003c/em\u003e. Sci Rep, 2019. 9(1): p. 17808.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEggington, J.M., et al., \u003cem\u003eA comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes\u003c/em\u003e. Clin Genet, 2014. 86(3): p. 229\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmendola, L.M., et al., \u003cem\u003ePerformance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium\u003c/em\u003e. Am J Hum Genet, 2016. 98(6): p. 1067\u0026ndash;1076.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, S.I., et al., \u003cem\u003eEffect of BRCA mutational status on survival outcome in advanced-stage high-grade serous ovarian cancer\u003c/em\u003e. J Ovarian Res, 2019. 12(1): p. 40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang, Y.W., \u003cem\u003eAssociation of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis\u003c/em\u003e. Medicine (Baltimore), 2018. 97(2): p. e9380.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNykamp, K., et al., \u003cem\u003eSherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria\u003c/em\u003e. Genet Med, 2017. 19(10): p. 1105\u0026ndash;1117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShao, K., et al., \u003cem\u003eComprehensive evaluation of BRCA1/2 variant interpretation ability among laboratories in China\u003c/em\u003e. J Med Genet, 2022. 59(3): p. 230\u0026ndash;236.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary Material","content":"\u003cp\u003eSupplementary Figures and Supplementary Table are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Germline BRCA 1/2 mutations, Epithelial ovarian cancer (EOC), Homologous recombination (HR) repair, Germline and somatic variants, Overall survival (OS)","lastPublishedDoi":"10.21203/rs.3.rs-6493572/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6493572/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTargeted sequencing has proven invaluable in evaluating BRCA1/2 and homologous recombination repair (HR) pathway genes in epithelial ovarian cancer (EOC). Comprehensive analysis of germline and somatic HR-related gene variants is critical to understanding their clinical significance. This study aims to explore the significance of such variants in Chinese EOC patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed 229 EOC patients using a 21-gene ovarian cancer panel and 141 patients with a 508-gene pan-cancer panel. Germline and somatic variants in the 21 HR-related genes were identified and interpreted. Variant frequencies were calculated, and overall survival (OS) and progression-free survival (PFS) were compared between carriers and non-carriers of BRCA1, BRCA2, and HR-related gene mutations. Responses to platinum-based chemotherapy and the PARP inhibitor Niraparib were also assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 229 patients, 17.9% carried BRCA1 mutations, 3.5% carried BRCA2 mutations, and 23.1% had mutations in HR-related genes. TP53 was the most common somatic mutation (66.4%). When both germline and somatic mutations were included, BRCA1 and BRCA2 mutation rates rose to 23.6% and 6.1%, respectively.\u003c/p\u003e\n\u003cp\u003eSurvival analyses (n=200) showed significantly longer OS for BRCA1/2 and HR-related mutation carriers (germline+somatic) compared to non-carriers under \"LP+\" (pathogenic/likely pathogenic variants) and \"VUS+\" (including variants of uncertain significance). Improved OS was observed for BRCA2 mutation carriers and BRCA1/2 somatic mutation carriers under VUS+ strategies. The hazard ratio for OS was lower in the VUS+ group, indicating enhanced predictive performance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBRCA1/2 and HR-related mutations are associated with improved OS and sensitivity to therapy. Integrating germline, somatic, and VUS data enhances survival prediction and treatment guidance, underscoring the need for comprehensive genetic assessments in EOC management.\u003c/p\u003e","manuscriptTitle":"Multigene germline and somatic testing for epithelial ovarian cancer in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 11:45:22","doi":"10.21203/rs.3.rs-6493572/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-07T04:23:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-23T13:52:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-19T06:07:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"156139355266484797949894055696529627984","date":"2025-05-12T05:43:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58680190663920843823084274343189423192","date":"2025-05-07T10:20:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230359939027673416202020782471316512046","date":"2025-05-06T22:58:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-06T10:07:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-30T04:55:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-22T04:26:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Precision Oncology","date":"2025-04-21T07:29:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7b7db97-d4af-4f19-b8a8-c52c4108e2fd","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":48193074,"name":"Biological sciences/Genetics/Cancer genetics"},{"id":48193075,"name":"Health sciences/Diseases/Cancer/Gynaecological cancer/Ovarian cancer"}],"tags":[],"updatedAt":"2025-08-18T16:05:42+00:00","versionOfRecord":{"articleIdentity":"rs-6493572","link":"https://doi.org/10.1038/s41698-025-01074-6","journal":{"identity":"npj-precision-oncology","isVorOnly":false,"title":"npj Precision Oncology"},"publishedOn":"2025-08-13 15:57:04","publishedOnDateReadable":"August 13th, 2025"},"versionCreatedAt":"2025-05-16 11:45:22","video":"","vorDoi":"10.1038/s41698-025-01074-6","vorDoiUrl":"https://doi.org/10.1038/s41698-025-01074-6","workflowStages":[]},"version":"v1","identity":"rs-6493572","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6493572","identity":"rs-6493572","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}