Hereditary ovarian cancer.

From an etiological point of view, ovarian cancer can be divided into two basic categories: hereditary and non-hereditary (sporadic). Most ovarian cancers (75–90%) are sporadic, which means that they arise as a result of the accumulation of somatic (non-hereditary) mutations acquired during a person’s lifetime and are confined to cells isolated from the tumour and are not passed on to offspring. A characteristic feature of sporadic tumours is that they usually occur at an older age and there is no family history of cancer [ 11 ]. Hereditary ovarian cancer includes about 10–25% of all ovarian cancer cases [ 11 , 12 ]. This cancer is associated with damage to genes responsible for repairing damaged DNA. About 24% of ovarian cancers are estimated to be associated with mutations in the germline, mainly the BRCA1 and BRCA2 genes (18%), and 6% with mutations in other genes. BRCA1 and BRCA2 are tumor suppressor genes responsible for repairing breaks in the DNA double strand by homologous recombination. This process involves the exchange of homologous chromosome fragments during the S and G2 phases of the cell cycle [ 13 ]. Mutations in the BRCA1 and BRCA2 genes lead to loss of heterozygosity. (i.e. loss of function of one of the two alleles tested), which promotes the process of carcinogenesis. Inheritance of predisposition to ovarian cancer as a result of mutations in the BRCA1 or BRCA2 genes occurs in an autosomal dominant manner, which means that inheriting a single mutant allele increases the risk of developing ovarian cancer [ 13 ]. According to Knudson’s “two-damage” theory, a cell with a germinal mutation (“first damage”) such as the BRCA1 mutation, functions normally as long as the second, normal allele. A somatic mutation of this allele (“second damage”) caused by environmental factors, causes a complete loss of gene function and, in the case of tumor suppressor genes leads to an accumulation of DNA damage and consequent loss of control of the cell which promotes the process of carcinogenesis [ 14 ]. In addition, mutations in the BRCA1 and BRCA2 genes are characterized by incomplete penetrance, which means that a person is a carrier of the gene mutation but does not show phenotypic features of the disease. Not all germline mutations lead to a predisposition to ovarian cancer [ 13 ]. According to the data, the prevalence of mutations in the BRCA1 and BRCA2 genes in ovarian cancer patients is about 14–18% in the germline and 7–8% in the somatic line [ 15 , 16 ]. To date, somatic BRCA1 mutations have been reported in 5–9% of sporadic ovarian cancer cases, while somatic BRCA2 genetic variants have been identified in 3–4% of tumors [ 17 ]. However, studies have shown that founder mutations cover only 48–65% of the germline mutation spectrum [ 16 ]. When it comes to inheriting mutations in the germline, first-degree relatives have a 50% risk of inheriting a mutation, while second-degree relatives have a 25% risk [ 18 ]. In 2019, Kowalik et al. investigated the frequency of BRCA1 and BRCA2 gene mutations in 201 unselected ovarian cancer tissues using Next-Generation Sequencing (NGS). Detected mutations were classified based on the ClinVar database according to the recommendations of the American the College of Medical Genetics (ACMG). Pathogenic mutations were detected in 24% (49/201) of the ovarian cancer samples tested, in the BRCA1 gene 36 (18%), in the BRCA2 gene 13 (6%). In order to check whether the mutations were somatic or germinal, 41 patients’ blood samples were tested. Based on the results, 35 detected mutations (17%; 35/201) were germline in origin, while 6 mutations (3%; 6/201) were somatic. VUS (Variants of unknown significance) were detected in 12 (6%) tissue samples. No mutations in the BRCA1 and BRCA2 genes were detected in the remaining 136 (68%) tumor tissue samples. The frequency of mutations was also analyzed based on the histological type of the tumor, and the results are shown in the Table 1 below [ 16 ]. Table 1 Frequency of detected pathogenic mutation in BRCA1/2 in studied histopathological subtypes of ovarian cancer in the study by Kowalik et al Histological subtype of ovarian cancer Cases Mutations in BRCA1/2 [%] Serous 155 45 29 Serous high grade 122 39 32 Serous low grade 33 6 18 Endometrioid 21 2 10 Clear cell 9 1 11 Mucinous 6 0 0 Undifferentiated 6 0 0 Mixed (serous + endometrioid) 4 1 25 Frequency of detected pathogenic mutation in BRCA1/2 in studied histopathological subtypes of ovarian cancer in the study by Kowalik et al The highest frequency of mutations in the BRCA1 and BRCA2 genes is observed in high-grade serous ovarian cancer (HGSOC), but genetic testing should not be limited to mutation testing only in HGSOC, because women with other histological subtypes (endometrial cancer, clear cell carcinoma, low-grade serous ovarian cancer - LGSOC) have a similar risk of mutations to HGSOC, i.e. 28% [ 19 , 20 ]. In carriers of germline (inherited) mutations in the BRCA1 and BRCA2 genes, the lifetime risk of ovarian cancer is 35–60% and 12–25%, respectively; these mutations also increase the risk of peritoneal and fallopian tube cancer. In addition, first- and second-degree relatives of ovarian cancer patients have a 3.6 and 2.9 times higher lifetime risk of ovarian cancer, respectively, than those without a family burden [ 4 , 21 ]. Assessing the clinical significance of a given mutation is a great challenge for geneticists. The currently used classification, recommended by the American College of Medical Genetics and Genomics (ACMG), distinguishes five classes of variant pathogenicity: pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign and benign, in clinical practice, pathogenic and probably pathogenic require more extensive diagnosis [ 13 , 22 ]. Currently, the ClinVar database has identified approximately 4,300 different germline variants in BRCA1 and 5,200 in BRCA2 that have been classified as pathogenic or likely pathogenic. Most of these (80%) result in premature stop codons that cause truncation of the nascent protein, frameshifts, and nonsense mutations. Missense variants account for about 10% of the identified variants [ 23 ]. Some hereditary cancer syndromes have also been linked to ovarian cancer, such as Lynch syndrome II ( a syndrome of hereditary non-polyposis-related colorectal cancer) is associated with a 4–12% risk of ovarian cancer. Lynch syndrome is associated with germline mutations in the genes : MLH1 , MSH2 , MSH6 , PMS2 , which are involved in mismatch repair (MMR) [ 21 ]. The Table 2 below shows the main syndromes included in hereditary ovarian cancer. Table 2 The main syndromes included in hereditary ovarian cancer Hereditary ovarian cancer syndromes Susceptibility genes Hereditary breast-ovarian cancer (HBOC) BRCA1 , BRCA2 Hereditary ovarian cancer, site-specific ovarian cancer, (HOC-ss) BRCA1 , BRCA2 Hereditary non-polyposis colorectal cancer (HNPCC) MLH1 , MSH2 , MSH6 , PMS2 The main syndromes included in hereditary ovarian cancer Characteristics that may indicate hereditary ovarian cancer are : (1) young age of onset ( less than 45 years old), (2) occurrence of neoplastic lesions on both ovaries at the same time, (3) previous history of other cancers, e.g. breast cancer. (4) Family history of malignancies (especially breast cancer or ovarian cancer in women and prostate cancer in men) [ 24 ]. Mutations in the BRCA1 and BRCA2 genes are associated with a high risk of ovarian and breast cancer and are called high-penetrance genes. The CHEK2 and PALB2 genes also predispose to the development of these cancers, but to a lesser extent, and are called low-penetrance genes. Mutations in the BRCA1 and BRCA2 genes occur in 1 in 300–800 people in the general population. However, due to the geographic and cultural history of Ashkhanazi Jews, the incidence of mutations in BRCA genes is much higher ( 1:40) than in the general population. This is connected with the so-called founder effect (in which a small group of people, isolated from a larger population, become founders of a new group), which leads to a decrease in genetic diversity and, as a result, to an increase in the frequency of mutations in a given group which are called founder mutations [ 25 , 26 ]. Ashkenazi founder mutations include two pathogenic BRCA1 mutations (c.185delAG and c.5382insC) and one pathogenic BRCA2 mutation (c.6174delT) [ 27 ]. Additionally, these three mutations account for 98–99% of identified mutations and are carried by approximately 2.6% of the Ashkenazi Jewish population [ 26 ]. In 2000, Górski et al. published an article in which they evaluated 66 families with a familial history of breast or ovarian cancer. Based on their research, they identified three mutations of the BRCA1 gene that are most common in the Polish population : c.5266dupC (5382insC) - insertion of an extra base - cytosine (C) in position 5266 in exon 20. c.4035delA (4153delA )- deletion or loss of a base - adenine (A) at position 4035 in exon 11. c.181T > G (300T > G) - a point mutation in which the thymine (T) base at position 181 is replaced by guanine (G) in exon 5. This results in a change of the amino acid cysteine to glycine in the encoded BRCA1 protein [ 28 , 29 ]. c.5266dupC (5382insC) - insertion of an extra base - cytosine (C) in position 5266 in exon 20. c.4035delA (4153delA )- deletion or loss of a base - adenine (A) at position 4035 in exon 11. c.181T > G (300T > G) - a point mutation in which the thymine (T) base at position 181 is replaced by guanine (G) in exon 5. This results in a change of the amino acid cysteine to glycine in the encoded BRCA1 protein [ 28 , 29 ]. The three mutations described above account for 91% of all mutations within the BRCA1 gene in the Polish population [ 28 ]. All of the mutations lead to a non-functional BRCA1 protein . These mutations are called founder mutations, which are mutations that occurred in one common ancestor and were passed on to his descendants, characterized by an identical DNA segment sequence in the affected individuals [ 15 , 30 ]. In 2024, Szwiec et al. identified another three mutations in the BRCA1 gene (3819del5, 185delAG and 5370 C > T, the use of which increases the mutation detection rate by 1.5% [ 31 ]. The mutations described above are called founder mutations, which are mutations that occurred in one common ancestor and were passed on to his descendants, characterized by an identical DNA segment sequence in the affected individuals. In BRCA2 : 6174delT, 886delGT, 4075delGT, 5467insT, 8138del5 [ 31 , 32 ]. In 2021, Łukomska et al. assessed the prevalence of founder mutations in genes associated with ovarian cancer among Polish women ( N  = 2095) with this cancer (see Table  3 ). Table 3 The prevalence of mutations in BRCA1 gene in research Łukomska et al. [ 33 ] Mutations Cases 5382insC (c.5266dupC) 124 (5.92%) 300T > G (c.181T > G) 48 (2.29%) 4153delA (c.4035delA) 10 (0.48%) 1806 C > T (c.1687 C > T) 6 (0.29%) 185delAG (c.68_69delAG) 8 (0.38%) 3819del5 (c.3700_3704del5) 14 (0.69%) 3875del4 (c.3756_3759delGTCT 3 (0.14%) 5370 C > T (c.5251 C > T) 1 (0.05%) The prevalence of mutations in BRCA1 gene in research Łukomska et al. [ 33 ] Other founder mutations have been identified in other populations, including French, Canadians, Icelanders, Norwegians, Austrians, Dutch, Russians and Hungarians : Norwegian: c.1016dup, c.1556del, c.3328_3229del, c.697_698del [ 34 ]. Hungarian: 300T > G, 185delAG, 5382insC [ 35 ]. Finnish: 3604delA, 3744delT, 4153delA, 4446 C→T, IVS11 + 3 A > G [ 36 ]. Russian: 5382insC, 4153delA, 185delAG, 300T > G [ 37 ]. Italian (Tuscany): c.3228_3229delAG, c.3285delA [ 38 ]. Norwegian: c.1016dup, c.1556del, c.3328_3229del, c.697_698del [ 34 ]. Hungarian: 300T > G, 185delAG, 5382insC [ 35 ]. Finnish: 3604delA, 3744delT, 4153delA, 4446 C→T, IVS11 + 3 A > G [ 36 ]. Russian: 5382insC, 4153delA, 185delAG, 300T > G [ 37 ]. Italian (Tuscany): c.3228_3229delAG, c.3285delA [ 38 ]. Chinese: 1081delG, 2371-2372delTG [ 39 ]. French Canadians: C4446T, R1443X, 4446 C > T, 2953delGTA + C in the BRCA1 gene and 2816insA, 6085G > T, 8765delAG in the BRCA2 gene [ 40 , 41 ]. Icelander 999del5 in BRCA1 [ 42 , 43 ]. Chinese: 1081delG, 2371-2372delTG [ 39 ]. French Canadians: C4446T, R1443X, 4446 C > T, 2953delGTA + C in the BRCA1 gene and 2816insA, 6085G > T, 8765delAG in the BRCA2 gene [ 40 , 41 ]. Icelander 999del5 in BRCA1 [ 42 , 43 ]. In addition, mutations in PALB2 , ATM , NBN , CHEK2 , RAD51C , RAD51D , BRIP1 and BARD1 genes, whose protein products are involved in the process of homologous recombination, may be linked in the process of ovarian cancer [ 44 ]. Different ethnic and geographical regions have a different spectrum of BRCA1 and BRCA2 mutations and their prevalence. Knowledge of the genetic structure of different populations is important for the development of an effective screening protocol and can provide a more efficient approach to individualising genetic testing. BRCA1 gene is located on the long arm of chromosome 17 at locus 17q21 and consists of 24 exons, 22 of which encode a protein consisting of 1863 amino acids and 220 kDa in mass. Exons 1 A and 1B contain two possible start sites for tracncryption and are not translated. [ 45 , 46 ]. It consists of several domains: N-terminal region - it carries zinc-binding finger domain RING ( Really Interesting New Gene ) binding protein BARD1 ( BRCA1 -associated RING domain protein). RING is required for the formation of the E3 ubiquitin ligase complex. Mutations of the BRCA1 RING domain that disconnect it from BARD1 and abolish E3 ligase activity are often associated with cancer predisposition. C terminus region consist of two phosphopeptide-binding BRCT ( BRCA1 C-terminal) domains [ 47 ]. N-terminal region - it carries zinc-binding finger domain RING ( Really Interesting New Gene ) binding protein BARD1 ( BRCA1 -associated RING domain protein). RING is required for the formation of the E3 ubiquitin ligase complex. Mutations of the BRCA1 RING domain that disconnect it from BARD1 and abolish E3 ligase activity are often associated with cancer predisposition. C terminus region consist of two phosphopeptide-binding BRCT ( BRCA1 C-terminal) domains [ 47 ]. BRCA2 is located on the long arm of chromosome 13 and has 27 exons, the largest being exon 11 (4.9 kb). BRCA2 encodes a protein that consists of 3418 amino acids (10.2 kb) [ 48 ]. BRCA2 participates in the recruitment of RAD51 filaments to the DNA double-strand break site and participates in damage repair through homologous recombination [ 49 ]. Depending on the location of the neoplastic transformation, we can distinguish several types of ovarian cancer. More than 90% of ovarian cancers are of epithelial origin and are called “ovarian carcinomas” because of the histological structure, we distinguish subtypes of ovarian cancer : Serous carcinoma (80% of cancers). Endometrioid carcinoma (10% of cancers). Clear cell carcinoma (5% of cancers). Mucinous carcinoma. Tumors of the transitional epithelium ( Brenner’s tumor). Type unclassified. Type mixed. Undifferentiated type [ 50 ]. Serous carcinoma (80% of cancers). Endometrioid carcinoma (10% of cancers). Clear cell carcinoma (5% of cancers). Mucinous carcinoma. Tumors of the transitional epithelium ( Brenner’s tumor). Type unclassified. Type mixed. Undifferentiated type [ 50 ]. In addition to epithelial neoplasms, we can also distinguish germ cell neoplasms. (dysgerminoma, arcinoma embryonale, yolk sac tumor, choriocarcinoma, teratoma and mixed germ cell tumor) and from germ cell cords ( Sertoli cell tumors, Leydig cell tumors, fibroma, fibrothecoma, thecoma. However, their incidence is negligible [ 4 , 21 ]. Individual tumors differ in their molecular characteristics, susceptibility to treatment, and are distinguished by immunohistochemical techniques. In 2014 International Federation of Gynaecology and Obstetrics (FIGO) updated the classification of ovarian cancer from 1998. The new classification takes into account : whether the tumor is unilateral or has a focus in both ovaries, invasion of the tumor capsule, presence of peritoneal exudate, presence of cancer cells in ascitic fluid, involvement of pelvic organs, invasion of other organs, metastases to lymph nodes, to distant organs, dissemination in the peritoneum [ 51 ]. Table 4 compares the FIGO scale with the Union for International Cancer Control (UICC) TNM classification: Table 4 Cancer of the ovary, fallopian tube and peritoneum: FIGO staging (2014) compared with TNM classificationa [ 4 , 51 ] TNM FIGO Primary tumor (T) TX Primary tumor cannot be assessed. T0 No evidence of primary tumor. T1 I Tumor limited to the ovaries (one or both). T1a IA Tumor limited to one ovary; capsule intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings. T1b IB Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings. T1c IC Tumor limited to one or both ovaries with any of the subcategories below (IC1-3). T1c1 IC1 Surgical spill. T1c2 IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface. T1c3 IC3 Malignant cells in ascites or peritoneal washings. T2 II Tumor involves one or both ovaries with pelvic extension below pelvic brim. T2a IIA Extension and/or implants on the uterus and/or tube(s). T2b IIB Extension to and/or implants in other pelvic tissues. T3 III Tumor involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis and/or retroperitoneal lymph node involvement. T3a IIIA2 Microscopic peritoneal metastasis beyond the pelvis with or without positive retroperitoneal lymph nodes. T3b IIIB Macroscopic peritoneal metastasis beyond the pelvis 2 cm or less in greatest dimension with or without positive retroperitoneal lymph nodes. T3c IIIC Macroscopic peritoneal metastasis beyond the pelvis > 2 cm in greatest dimension including extension to liver capsule or spleen without parenchymal involvement of those organs and with or without positive retroperitoneal lymph nodes. Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed. N0 No regional lymph node metastasis. N0(i+) Isolated tumor cells in regional lymph node(s) ≤ 0.2 mm. N1 IIIA1 Positive (histologically confirmed) retroperitoneal lymph nodes. N1a IIIA1(i) Metastasis ≤ 10 mm in greatest dimension. N1b IIIA1(ii) Metastasis more than 10 mm in greatest dimension. Distant metastasis (M) M0 No distant metastasis. M1 IV Distant metastasis including cytology-positive pleural effusion; liver or splenic parenchymal involvement; extra-abdominal organ involvement including inguinal lymph nodes; transmural intestinal involvement. M1a IVA Pleural effusion with positive cytology. M1b IVB Liver or splenic parenchymal metastases; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine. Cancer of the ovary, fallopian tube and peritoneum: FIGO staging (2014) compared with TNM classificationa [ 4 , 51 ] Ovarian cancer can also be classified into two main types based on differences in etiology, pathogenesis, histopathology and clinical course : Type I : Type I cancers include : low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC), clear cell carcinoma (CCC). They often arise from precancerous lesions, such as endometriosis, and are characterized by a slower growth rate and a milder course. Cancerous lesions are usually limited to one ovary and have a better prognosis than type II tumors. They are usually genetically stable, characterized by various somatic mutations in the genes : KRAS , BRAF , PTEN , PIK3CA , CTNNB1 , ARID1A , PP2R1A and rarely a mutation in TP53 [ 52 ]. Type I cancers include : low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC), clear cell carcinoma (CCC). They often arise from precancerous lesions, such as endometriosis, and are characterized by a slower growth rate and a milder course. Cancerous lesions are usually limited to one ovary and have a better prognosis than type II tumors. They are usually genetically stable, characterized by various somatic mutations in the genes : KRAS , BRAF , PTEN , PIK3CA , CTNNB1 , ARID1A , PP2R1A and rarely a mutation in TP53 [ 52 ]. Type II : Type II cancers include : high-grade serous carcinoma (HGSC), Undifferentiated carcinoma (NOS), are characterized by a very rapid growth rate and aggressive course. More than 75% of type II cancers are diagnosed at high clinical stages. 95% of Type II cancers have a TP53 mutation, and very often somatic and germline mutations in BRCA1 and BRCA2 [ 52 ]. Type II cancers include : high-grade serous carcinoma (HGSC), Undifferentiated carcinoma (NOS), are characterized by a very rapid growth rate and aggressive course. More than 75% of type II cancers are diagnosed at high clinical stages. 95% of Type II cancers have a TP53 mutation, and very often somatic and germline mutations in BRCA1 and BRCA2 [ 52 ]. In ovarian cancer, there are no pathognomonic symptoms and early symptoms (if any) usually include gastrointestinal or abdominal complaints such as bloating, indigestion, constipation, hiccups, belching, a feeling of fullness in the abdomen or slow loss of appetite. Most often, ovarian cancer patients arrive for treatment at stages of significant progression, with symptoms of a tumor mass in the pelvis (abdominal pain, bloating, sacral pain, dysuria and dyspareunia) [ 51 , 52 ]. Ascites formation occurs as a result of tumor-induced neovascularization and increased permeability of microvessels, as well as impaired lymph drainage from the peritoneal cavity due to obstruction of lymph vessels by tumor cells. The formation of ascites enhances trans-coelomic metastasis because it facilitates the formation of micro metastases of ovarian cancer cells through the peritoneum [ 51 , 52 ]. Ovarian cancer is diagnosed based on the results of pathological examination of material collected during the initial surgical procedure. In exceptional cases, when surgery is not possible, the diagnosis can be made based on material collected during a peritoneal or pleural fluid biopsy and liver metastases [ 53 ]. An important role in the diagnosis of ovarian cancer is played by the subject and physical examination, which includes : transvaginal ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) and testing of tumor markers (CA125, HE4, CEA, CA 19 − 9) [ 54 ]. Genetic testing plays a key role in the diagnosis, prevention and treatment of ovarian cancer. In addition, the detection of germinal mutations in the BRCA1/BRCA2 genes, allows the patient’s family to receive appropriate care (genetic consultation, genetic testing, regular monitoring, surgical prevention and education and support for family members). This allows for early detection of this cancer and appropriate preventive measures. Typically, testing begins with simple screening techniques that identify population-specific founder mutations. These include Sanger sequencing, they allow identification, only selected pathogenic variants. A negative result from screening should be expanded using the Next Generation Sequencing (NGS) method, which allows the examination of entire coding sequences in BRCA1 and BRCA2 and other genes key in the etiopathogenesis of ovarian cancer in a single test [ 55 ]. Currently, we do not have effective methods or screening tests to detect ovarian cancer early. Existing techniques are not sensitive or specific enough to detect this type of cancer at an early stage, making it difficult to treat it quickly and effectively. Therefore, research into new diagnostic methods is critical to improve early detection and increase the chances of successful treatment. By analyzing mutations in genes such as BRCA1 and BRCA2, it is possible to detect the risk earlier and take appropriate preventive measures. Treatment of ovarian cancer is difficult because of the heterogeneity of this tumor. A single histologic type can consist of several molecular subtypes that differ in prognosis, response to treatment and malignancy [ 56 ]. The mainstay of therapy for ovarian cancer is therapy, which includes : surgical treatment and chemotherapy. The goal of surgery is complete cytoreduction, that is, complete elimination of visible tumor lesions. If it is impossible to achieve complete cytoreduction, one should aim for optimal cytoreduction (residual disease < 1 cm). The treatment plan will depend on: - The type of cancer the patient has, - The stage and malignancy of the cancer, - The patient’s general health, - The patient’s personal preferences ( preservation of fertility). - The type of cancer the patient has, - The stage and malignancy of the cancer, - The patient’s general health, - The patient’s personal preferences ( preservation of fertility). The main drugs used in the treatment of ovarian cancer include : platinum derivatives (cisplatin, carboplatin), taxanes (paclitaxel and docetaxel), angiogenesis inhibitors (bevacizumab) and others [ 57 ]. In addition, PARP Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) play an important role in the treatment of hereditary ovarian cancer in particular. Mutations in BRCA1/BRCA2 contribute to homologous recombination deficiency (HRD), which makes it difficult to repair errors in the genetic material and leads to their accumulation. Which causes cancers with mutations in these genes to become dependent on other DNA repair mechanisms, switching from one DNA repair mechanism to another. The mechanism of action of PARP inhibitors involves (olaparib, niraparyb, rucaparib, talazoparib) blocking PARP enzymes on DNA strands, resulting in blocking the repair process of single DNA breaks and leading to the accumulation of lethal double DNA breaks for the cell, which can be repaired by homologous recombination. In patients with hereditary ovarian cancer, there is a deficit in this repair mechanism, which leads to the accumulation of DNA damage and eventually causes cell death. Thus, the use of PARP inhibitors has an important role in the treatment of hereditary ovarian cancer [ 58 , 59 ]. The standard surgical procedure for the treatment of advanced ovarian cancer is primary debulking surgery (PDS), which involves maximal excision of the tumor mass prior to the initiation of chemotherapy. Reducing the size of the of the tumor increases the effectiveness of subsequent chemotherapy and improves the patient’s prognosis [ 59 ]. In cases where PDS is not possible, interval debulking surgery (IDS) - which involves the initial administration of neoadjuvant platinum derivative-based chemotherapy. ( 3 cycles) followed by cytoreductive surgery. It is used when performing primary cytoreductive surgery is impossible due to the patient’s medical condition, the large extent of the cancerous lesions, etc. IDS is aimed at reducing the tumor mass and then cytoreductive surgery [ 60 , 61 ]. Salpingo-oophorectomy ( bilateral resection of the ovaries and fallopian tubes) reduces the risk of ovarian cancer by almost 80% and breast cancer by 50%. NCNN recommends RRSO ( Risk - Reducing Salpingo – Oophorectomy) in women who have pathogenic mutations in the BRCA1 , BRCA2 , BRIP1, RAD51C or RAD51D or any of the Lynch Syndrome Genes [ 62 ]. For female BRCA1 mutation carriers, risk-reducing salpingo-oophorectomy (RRSO) is recommended at age 35–40 or after the end of reproductive plans. The option of delaying RRSO until age 40–45 in women with BRCA2 mutations may be considered, as the average age of onset appears to be later by about 8–10 years compared to BRCA1 mutation carriers and possibly later in BRIP1 , RAD51C and RAD51D mutation carriers. It is important to analyze multigenerational family history and pay attention to the age of ovarian cancer incidence in the family and adjust this recommendation [ 62 , 63 ].

Hereditary ovarian cancer is a serious health challenge that requires a comprehensive approach to both diagnosis and treatment of patients. Genetic testing is an integral part of the diagnosis and treatment of patients with ovarian cancer. The identification of pathogenic germline variants, particularly in BRCA1 , BRCA2 and other DNA repair-related genes, allows patients to qualify for personalised therapy, including therapies targeting homologous recombination defects. At the same time, the detection of a mutation in a patient is of significant importance to her family members. First-degree relatives may be offered genetic counselling and testing for the same mutation. In individuals with a confirmed hereditary predisposition, appropriate preventive measures can be implemented and oncological surveillance increased. However, further research into hereditary ovarian cancer is necessary to fully understand its pathophysiological mechanisms and develop even more effective diagnostic and therapeutic strategies.

The number of cancer patients continues to rise, and cancer is the second leading cause of death [ 8 ]. Based on data from the GLOBOCAN database, worldwide there were : 9 664 889 cases of malignant cancers ( mortality of 4 313 548) among women, including 324 603 ovarian cancers - Asia − 178 223 (54,9%), Europe − 69 472 (21,4%), Africa − 25 760 (7,9%), Northern America – 24 484 (7,5%) and others – 26 664 ( 8,2%), mortality - Asia − 109 547 (52,9%), Europe − 46 232 (22,3%), Africa − 18 024 (8,7%), Northern America − 15 554 (7,5%), and others. In Poland in 2022, there were 99,535 cases of cancer among women (4,678 developed ovarian cancer – 4,7%) while 54,250 women died ( 3,206 from ovarian cancer – 5,9%). These data show that ovarian cancer, although not the most common cancer, is a significant problem due to its high mortality rate (see Figs. 1 , 2 , 3 , 4 , 5 and 6 ). Fig. 1 Incidence of malignant tumors among women ( breakdown by continent ) 2022 Incidence of malignant tumors among women ( breakdown by continent ) 2022 Fig. 2 Mortality from malignant tumors among women ( breakdown by continent ) 2022 Mortality from malignant tumors among women ( breakdown by continent ) 2022 Fig. 3 Incidence of ovarian cancer ( breakdown by continent) 2022 Incidence of ovarian cancer ( breakdown by continent) 2022 Fig. 4 Ovarian cancer mortality ( breakdown by continent) 2022 Ovarian cancer mortality ( breakdown by continent) 2022 Fig. 5 Incidence of malignant tumors in Poland among women in 2022 Incidence of malignant tumors in Poland among women in 2022 Fig. 6 Malignant cancer mortality in Poland among women in 2022 Malignant cancer mortality in Poland among women in 2022 In 2011, Walsh et al. published a study in which 360 women were examined for mutations in 12 genes associated with hereditary cancers. Subjects included 273 women with ovarian carcinomas, 48 with peritoneal carcinomas, 31 with fallopian tube carcinomas, and 8 with synchronous endometrial and ovarian carcinomas. Among all the examined individuals, 85 mutations were observed in 12 genes studied, including 40 (11.1%) in BRCA1 , 23 (6.4%) in BRCA2 , and 22 (6.1%) in 10 other genes ( CHEK2 , BRIP1 , TP53 , RAD51C , RAD50 , PALB2 , NBN , MSH6 , MRE11 , BARD1 ) [ 9 , 10 ]. The results of the study are presented in the Figure 7 below: Fig. 7 Pie chart showing the frequency of mutations in 12 genes in the work of Walsh et al Pie chart showing the frequency of mutations in 12 genes in the work of Walsh et al The high percentage of detected mutations (85/360–23.61%) in the study group emphasises the importance of genetic testing. Furthermore, most of the detected mutations concerned high-risk genes ( BRCA1 and BRCA2 ), but also other genes, which proves that broad genetic panels allow for the detection of additional clinically significant mutations that could be overlooked in the analysis of BRCA1/2 alone. Identifying such mutations may influence decisions regarding treatment, prevention and screening in patients and their families.

Ovarian cancer ranks third (after cervical cancer and endometrial cancer) as the most common gynecological cancer. However, compared to other gynecological cancers, ovarian cancer has the highest mortality rate (it accounts for about 60–70% of deaths from all gynecological cancers) [ 1 , 2 ]. For years I have observed an increase in the incidence of ovarian cancer in developed countries compared to less developed countries. Probably the reason for this phenomenon is the fact that life expectancy is increasing in highly developed countries, and as is known, the average age of ovarian cancer is about 65 years and 75% of all ovarian cancers are observed after menopause [ 3 ]. In advanced ovarian cancer, tumor metastasis occurs, including to the peritoneal cavity and its organs and via lymphatic and blood vessels [ 4 , 5 ]. Approximately 90% of ovarian cancers occur sporadically, meaning that the cancer patient has no close relatives with cancer, and the disease occurred in the patient as a result of the accumulation of damage to the genetic code over a lifetime. The most significant risk factor for ovarian cancer is genetic. The highest risk of the disease is associated with the presence of mutations in the BRCA1 and BRCA2 genes. These mutations are responsible for the hereditary occurrence of ovarian cancer and breast cancer. The occurrence of locally specific ovarian cancer in Lynch II syndrome is also known to be associated with mutations in the DNA repair genes MSH2 and MLH1 . The familial form of cancer is characterized by an increased incidence of cancer in some families compared to the general population, but without a specific pattern of inheritance. The familial or hereditary form accounts for 15–24% of ovarian cancer cases, depending on the population, and the majority (10–18%) are associated specifically with mutations in the BRCA1 or BRCA2 genes [ 6 , 7 ].