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Review
Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes
  1. Antonella Pietragalla1,
  2. Martina Arcieri2,
  3. Claudia Marchetti1,
  4. Giovanni Scambia1,3 and
  5. Anna Fagotti1,3
  1. 1 Department of Woman, Child, and Public Health, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
  2. 2 Department of Obstetrics and Gynecology, University of Eastern Piedmont, Novara, Italy
  3. 3 Catholic University of Sacred Heart, Rome, Italy
  1. Correspondence to Professor Giovanni Scambia, Department of Women, Child, and Public Health, Fondazione Policlinico Universitario A Gemelli IRCCS, 00168 Roma, Italy; giovanni.scambia{at}policlinicogemelli.it

Abstract

Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20–25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.

  • ovarian cancer
  • homologous recombination
  • BRCA1 Protein
  • BRCA2 Protein

https://doi.org/10.1136/ijgc-2020-001556

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    Introduction

    The incidence of new cases of epithelial ovarian cancer is approximately 9.5 per 100 000 person years in Europe1 and represents the leading cause of death among gynecological malignancies. Approximately 23% of ovarian carcinomas are associated with hereditary conditions.2–4 Approximately 10–15% of all epithelial ovarian tumors5–8 are caused by germline mutations in BRCA genes and 20–25% of high grade serous subtype develop in patients who harbor a germline BRCA mutations.9–11 The mutations in BRCA1 or BRCA2 are associated with an increased lifetime risk of developing breast and ovarian cancer, as well as pancreatic cancer, melanoma, and possibly serous/serous-like uterine cancer. There are limited data suggesting a slightly increased risk of serous endometrial cancer among BRCA1 mutation carriers,12 but the clinical significance of this is still unclear. The cumulative risk of breast and ovarian cancers to age 80 years is approximately 72% and 44% for BRCA1 and 69% and 17% for BRCA2 mutation carriers, respectively.13 For the past 20 years, mutations in BRCA genes were considered the cause of the majority of hereditary ovarian carcinomas. Currently, as a result of next generation sequencing, at least 16 other genes associated with hereditary ovarian cancer have been discovered,4 leading to growing evidence of related rare syndromes associated with gynecologic cancers.

    The identification of a hereditary mutation is important for both healthy carriers and patients with ovarian cancer. In the first group, it may justify more intensive and personalized screening and prophylactic surgery, while in patients with cancer, these genetic mutations may lead to potential target therapy (such as poly(ADP-ribose) polymerases inhibitors). The purpose of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to discuss the risk assessment, genetic testing, prevention strategies, and potential therapeutic implications.

    DNA Repair Systems

    Most of the genes associated with the pathogenesis of non-BRCA related hereditary ovarian cancer are involved in the DNA damage repair system. A brief description of their mechanism of action offers clarity in their association and correlation with cancer. During the normal cell cycle, the maintenance of genomic stability is supported by the recognition and subsequent DNA damage repair from several genes. DNA damage is an alteration in the structure of DNA: single strand and double strand cleavage of the DNA. There are five key mechanisms of DNA damage repair: base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, and non-homologous end joining repair (Figure 1). Base excision repair, nucleotide excision repair, and mismatch repair genes are involved in repairing single strand breaks, where the complementary strand has no defect.14 Conversely, homologous recombination and non-homologous end joining repair genes mainly act in repairing double strand breaks.

    Figure 1
    Figure 1

    (A) Repair pathway for single strand breaks: base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). (B) Repair pathway for double strand breaks: homologous recombination (HR) and non-homologous end joining repair (NHEJ).

    Base excision repair mainly repairs non-bulky lesions produced by alkylation, oxidation, or deamination of bases. It belongs to the most important family of proteins involved in DNA damage repair, the poly(ADP-ribose) polymerases. Indeed, poly(ADP-ribose) polymerases have several functions, such as repair of single strand and double strand DNA damage and repair of non-DNA cellular activities, such as chromatin edit and transcription regulation. The poly(ADP-ribose) polymerase family is composed of 17 different nuclear enzymes but only PARP-1, PARP-2, and PARP-3 have a known function in DNA repair. PARP-1 protein is the most involved in the DNA repair pathway for both single and double strand DNA breaks. It has a domain allowing protein–protein interactions, such as its interaction with BRCA1, and a catalytic domain responsible for the enzymatic function. PARP-1 takes part in single strand DNA repair through the base excision repair pathway, resulting in replacement of a single damaged base to restore DNA integrity.15 Poly(ADP-ribose) polymerase binds DNA to the site of the excised base and recruits other DNA repair proteins.16 17 The absence of poly(ADP-ribose) polymerase and/or other proteins involved in the base excision repair pathway is not lethal, but the cell upregulates other repair pathways. Single strand breaks lead to stalled replication forks with resultants double strand breaks and consequential activation of homologous recombination and non-homologous end joining repair. Also, PARP-1 has a role in homologous recombination and non-homologous end joining repair systems: it repairs by binding to sites of double strand breaks and recruiting poly(ADP-ribose) binding homologous recombination proteins15 and it downregulates non-homologous end joining repair by inactivating crucial DNA dependent protein kinases.14

    In the single strand DNA damage repair system, nucleotide excision repair removes a variety of forms of DNA damage, including photoproducts induced by ultraviolet and other bulky lesions.

    The main specificity of mismatch repair is primarily for base–base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. Mismatch repair proteins are MLH1, MSH2, MSH6, and PMS2; epithelial cell adhesion molecule is a regulator of MSH2.18 The loss of function in mismatch repair genes leads to hypermutation and high microsatellite instability as a result of failure to repair mutations in short repetitive DNA sequences that predispose to the development of several types of cancer. Microsatellites are composed of 1–6 base pairs repeated with high risk for replication errors. They are contained in several oncogenes and tumor suppressor genes.

    DNA double strand breaks are corrected by the homologous recombination and non-homologous end joining repair pathways. DNA double strand breaks represent the most lethal insult to the genome and, if not repaired, cause genomic instability and cell death. Homologous recombination allows for a highly conservative repair system, while non-homologous end joining repair represents a less accurate mechanism but it allows for minimizing DNA damage when homologous recombination is not effective4. Homologous recombination repairs double strand breaks during the S and G2 phases and uses a homologous DNA template.19 In the homologous recombination pathway, beyond BRCA1 and BRCA2, several proteins are involved, such as RAD51C, RAD51D, CHEK2, BARD1, ATM, ATR, EMSY, Fanconi anemia proteins (BRIP1 and PALB2), and MRN complex. Another important gene is PTEN (phosphatase and tensin homolog), a tumor suppressor gene that regulates the PI3K pathway involved in cell proliferation.20 It is not certain whether PTEN mutation causes homologous recombination deficiency.21

    If there is a defect in one of the proteins involved in homologous recombination, the double strand breaks are repaired through non-homologous end joining repair, an imperfect and error prone mechanism. This could determine new genetic defects and, consequently, the development of cancer. The most important proteins involved in this pathway are the MRN complex composed by RAD50, Mre11, and NBS1. As mentioned, this complex is also involved in the homologous recombination system. The DNA repair system is a very complex mechanism: each pathway intersects with the others through proteins that act in different mechanisms. It is important to underline that each gene coding for proteins involved in the DNA repair system could be a candidate for ovarian cancer susceptibility.

    In particular, the BRCAness profile is represented by phenotypic changes led by defects in the homologous recombination system that attains similar outcomes to those with germline BRCA mutations, in the absence of a specific BRCA mutation. Patients with these mutations could develop ovarian cancer with similar features and behavior to BRCA related tumors, including platinum sensitivity and improved disease free survival. Additionally, an increased risk of developing breast cancer is described.4 19 Approximately 50% of high grade serous ovarian cancers are characterized by germline or somatic homologous recombination deficiency which include mutations in BRCA1-2 (20%), epigenetic silencing of BRCA1 (11%), amplification or mutation of EMSY (8%), deletion of PTEN (7%), mutations in Fanconi anemia genes (5%), hypermethylation of RAD51C (3%), and mutations in ATM or ATR (2%)8 21 (Figure 2). Other genes not directly involved in the previously mentioned mechanisms could be responsible for ovarian cancer susceptibility, such as TP53, STK11, EXT, and PTCH1 genes. They code for proteins involved in cell proliferation, apoptosis, and genomic stability.

    Figure 2
    Figure 2

    Susceptibility genes and their prevalence in hereditary ovarian syndromes. HR, homologous recombination.

    TP53 is a cancer suppressor gene, also defined as the 'guardian of the genome', that codes for a transcription protein (p53) implicated in the regulation of cell growth and in the apoptosis pathway. STK11 (serine–threonine protein kinase 11) is an oncosupressor gene located on chromosome 19p13.3, participating in membrane bonding and apoptosis, and it also negatively regulates the mammalian target of rapamycin (mTOR) pathway.

    Hereditary Ovarian Cancer Syndromes Beyond BRCA

    Patients with hereditary ovarian cancer syndrome have a genetic predisposition at high penetrance caused by a mutation in the genes involved in DNA repair systems or in cell proliferation, apoptosis, and genomic stability (Table 1).

    View this table:
    Table 1

    Genetic mutation and clinical implications

    Mismatch Repair Genes and Lynch Syndrome

    Lynch syndrome is an autosomal dominant syndrome characterized by germline mutations in the mismatch repair genes or by epithelial cell adhesion molecule deletions.18 It is estimated that approximately 0.39% of the general population carry a mutation in mismatch repair genes. Patients with Lynch syndrome have inherited one mutated allele of a mismatch repair gene while the loss of the second allele happens somatically for mutation, methylation, or a combination of both.4 Lynch syndrome is associated with an increased risk of developing numerous cancers, such as colorectal cancer (hereditary non-polyposis colorectal cancer), endometrial cancer, epithelial ovarian cancer, and other cancers including stomach, small bowel, pancreatic and genitourinary tumors, brain cancer (glioblastoma multiforme), and skin manifestations (sebaceous adenomas). The major risk with Lynch syndrome is for colorectal cancer and endometrial cancer, with a lifetime risk of approximately 30–50% and 40–50%, respectively.22

    Lynch syndrome is the second most common cause of hereditary epithelial ovarian cancer, responsible for approximately 0.5–3% of epithelial ovarian cancer23 and for about 10–15% of hereditary ovarian cancers.2 18 24 In the Lynch syndrome population, the cumulative risk of ovarian cancer is approximately 8–10%,22 compared with a risk of 1.4% in the general population.25 The cumulative ovarian cancer risk is approximately 10–20% for MLH1, 17–24% for MSH2, and 8–13% for MSH6 mutation carriers while the epithelial ovarian cancer risk is similar to the general population for PMS2 mutation carriers.23

    Epithelial ovarian cancers linked to Lynch syndrome are generally associated with a better prognosis and are diagnosed in the early stages (International Federation of Gynecology and Obstetrics staging I/II in approximately 85% of cases) but they occur with an earlier onset (median age 46–50 years) compared with sporadic epithelial ovarian cancer.2 26 The prognosis may be better regardless of stage compared with BRCA mutation carriers or the general population.23 The most common histotype found in the setting of Lynch syndrome is endometrioid adenocarcinoma, followed by clear cell or serous type, depending on the series.2

    Genetic testing for Lynch syndrome is recommended after screening through Amsterdam and Bethesda criteria (Box 1). The modified Amsterdam criteria clinically define a family with possible Lynch syndrome who should be referred directly for a germline DNA test, preferably starting from an affected individual. Instead, Bethesda guidelines are used to screen the subset of individuals with colon or endometrial cancer by performing somatic analysis on the tumor. The European Society for Medical Oncology guidelines recommend annual endometrial evaluation by pelvic ultrasound with or without biopsies from age 30–35 years in patients with Lynch syndrome.27 The efficacy of this regimen still remains uncertain. According to the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology guidelines, women with Lynch syndrome who have completed childbearing should be counseled about total hysterectomy and bilateral salpingo-oophorectomy to reduce the risk of both endometrial and ovarian cancer. The timing of risk reducing surgery may be individualized based on family history and comorbidity.27 28

    Box 1

    Testing criteria for Lynch syndrome

    Amsterdam II criteria56: clinical criteria for identifying Lynch syndrome in a family (sensitivity 23%, specificity 98%)

    • Three or more relatives with Lynch syndrome associated cancers (colorectal cancer, endometrial cancer, small bowel cancer, transitional cell carcinoma of the ureter, or renal pelvis), one of whom must be a first degree relative of the other two. Familial adenomatous polyposis should be excluded in the colorectal cancer cases.

    AND

    • Lynch syndrome associated cancers involving at least two generations.

    AND

    • At least one cancer diagnosed before the age of 50.

    Revised Bethesda guidelines22 (identify individuals with colon cancer or endometrial cancer to consider for further testing for possible Lynch syndrome) (sensitivity 82%, specificity 77%)

    • Colorectal cancer diagnosed before the age of 50.

    • Presence of synchronous, metachronous colorectal or other hereditary non-polyposis colorectal cancer (HNPCC) associated tumors, regardless of age (ie, colorectal cancer, endometrial cancer, gastric, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors (usually glioblastoma, as seen in Turcot syndrome), sebaceous gland adenomas, keratoacanthomas in Muir–Torre syndrome, and small bowel carcinoma).

    • Colorectal cancer with high microsatellite instability-like histology (presence of tumor infiltrating lymphocytes, Crohn's-like lymphocyticreaction, mucinous/signet ring differentiation, or medullary growth pattern) diagnosed before the age of 60.

    • Colorectal cancer diagnosed in a patient with one or more first degree relatives with an HNPCC related tumor, with one of the cancers diagnosed before the age of 50.

    • Colorectal cancer diagnosed in a patient with two or more first or second degree relatives with HNPCC related tumors, regardless of age.

    The germline or somatic mismatch repair deficiency characterizes approximately 10–12% of unselected epithelial ovarian cancers. In particular, it is found in 19.2% of endometrioid, 16.9% of mucinous, 11.5% of clear cell, and 1–8% of serous histologic subtypes. Therefore, the recently published American Society of Clinical Oncology guidelines29 regarding germline and somatic tumor testing in epithelial ovarian cancer recommend the routine assessment of mismatch repair deficiency in clear cell, endometrioid, and mucinous ovarian, fallopian, and primary peritoneal cancer. Notably, clear cell ovarian cancers with microsatellite instability are more immunogenic compared with those without mismatch repair deficiency, thus benefiting from immune checkpoint blockade.30 Indeed, the use of pembrolizumab, a monoclonal anti-programmed cell death-1 antibody, has been approved in the setting of recurrent disease in patients with mismatch repair deficiency phenotype or genotype, regardless of the primary site.29 Therefore, screening for this defect represents an attempt at personalized treatment, while searching for cancer predisposition.

    PTEN and Cowden Syndrome

    PTEN is a tumor suppressor gene, located on chromosome 10q23.3. Its loss of function is frequently present as a somatic or germline mutation in different tumor types. Germline mutations of PTEN causes Cowden syndrome. In PTEN the most common mutation in ovarian cancer is gene deletion20 but its role in ovarian cancer susceptibility21 is not definitely demonstrated. The epithelial ovarian cancer type I (low grade, relatively indolent, and genetically stable tumors that typically arise from precursor lesions, such as endometriosis or borderline tumors) are characterized by KRAS, BRAF, PTEN, and beta-catenin somatic mutations. Somatic mutations of PTEN in combination with KRAS mutations seem to predispose to invasive and metastatic endometrioid ovarian cancer.20 Efforts for targeted therapies against such frequent mutations in epithelial ovarian cancer type I have been unsatisfactory thus far. No ovarian cancer risk reducing surgery should be performed in PTEN pathogenic variant carriers. Instead, PTEN mutation carriers have an increased endometrial cancer risk: the overall risk is approximately 5–10%.31

    Tp53 and Li-Fraumeni Syndrome

    The TP53 gene, located on chromosome 17p13, is a cancer suppressor gene. TP53 is the most frequently acquired mutated gene in cancer, and approximately 97% of sporadic high grade serous ovarian carcinomas show a pathogenic mutation of TP53.32 Cancers with acquired TP53 mutations are more aggressive with worse survival rates, increased resistance to chemotherapy, and elevated relapse rates.4 TP53 germline mutations characterize Li–Fraumeni syndrome, an autosomal dominant syndrome with high penetrance (Box 2).

    Box 2

    Testing criteria for Li-Fraumeni syndrome

    Classic Li-Fraumeni syndrome criteria (all of the following)57:

    • An individual diagnosed before the age of 45 with a sarcoma.

    • A first degree relative diagnosed before the age of 45 with cancer.

    • A first or second degree relative in the same lineage with cancer diagnosed before the age of 45 or a sarcoma at any age.

    Chompret criteria58 59:

    • A proband with a tumor from Li-Fraumeni syndrome criteria tumor spectrum (eg, soft tissue sarcoma, brain tumor, osteosarcoma, premenopausal breast cancer, adrenocortical carcinoma, leukemia, or lung bronchoalveolar cancer), before the age of 46.

    AND

    • At least one first or second degree relative with any of Li-Fraumeni syndrome criteria related cancers (except breast cancer if the proband has breast cancer) before the age of 56 or with multiple tumors at any age.

    • A proband with multiple tumors (except multiple breast tumors), two of which belong to Li-Fraumeni syndrome criteria tumor spectrum with the initial cancer occurring before the age of 46.

    • A proband with adrenocortical carcinoma, or choroid plexus carcinoma or rhabdomyosarcoma of the embryonal anaplastic subtype, at any age of onset, regardless of family history.

    • A female proband with breast cancer before the age of 31 and a negative family history.

    Somatic tumor tissue with:

    • TP53 pathogenic variant with an allele frequency of ~50% or >50%.

    • Absent or decreased p53 positivity by immunohistochemistry.

    Patients with Li-Fraumeni syndrome have inherited one mutated allele while the loss of the second allele happens somatically. Missense mutation is the most common mutation in germline and sporadic cases (~75%). Li-Fraumeni syndrome is a highly penetrant rare syndrome with a lifetime risk of cancer exceeding 90% for women.33 It causes a wide spectrum of malignancies, often multiple primary cancers (15–35%), with an onset before the age of 30. The most common Li-Fraumeni syndrome associated tumors are breast cancer, sarcoma, brain, and adrenocortical carcinoma while leukemia and lung, colorectal, skin, gastric, and ovarian cancers are less frequent.2 34 Nowadays, it is not clear if these less frequent cancers have a higher incidence in Li-Fraumeni syndrome or if their presence is due to chance. In fact, the overall risk of epithelial ovarian cancer seems to be similar to that of the general population.35 However, ovarian cancer in Li-Fraumeni syndrome could have an earlier onset: the median age seems to be 39.5 years, compared with 64.3 years for sporadic cases.2 4 International guidelines do not recommend any epithelial ovarian cancer risk reducing surgery in these families.

    STK11 and Peutz-Jeghers syndrome

    STK11 is an oncosupressor gene located on chromosome 19p13.3.33 Germline mutations of STK11 are linked to Peutz-Jeghers syndrome, a rare (1:20 000) autosomal dominant disease.36 It is characterized by mucocutaneous pigmentation, gastrointestinal hamartomas, and an increased risk of colorectal, pancreatic, gallbladder, breast, non-epithelial ovarian and cervical neoplasms. Specific Peutz-Jeghers syndrome ovarian tumors are non-epithelial, benign sex cord tumors with annular tubules, dysgerminomas, granulosa cell, Brenner, and Sertoli cell tumors. Benign sex cord tumors with annular tubules, unlike the sporadic cases, are often multifocal, bilateral, and small. In Peutz-Jeghers syndrome, the cumulative risk of benign sex cord tumors with annular tubules is approximately 18–21%.18 Moreover, patients with Peutz-Jeghers syndrome have an estimated 15–30% lifetime risk of minimal deviation adenocarcinoma, also known as adenoma malignum of the cervix.36

    According to the NCCN guidelines, women with Peutz-Jeghers syndrome should undergo annual pelvic examinations, transvaginal ultrasound, and Pap smear, beginning at ages 18–20 years.37

    Rare Hereditary Syndromes Predisposing to Ovarian Cancer

    The lifetime risk of developing an ovarian cancer is approximately 2% for carriers of the following mutations: EXTs gene mutations cause Ollier’s syndrome, related to an increased risk of ovarian granulosa cell tumor; and PTCH1 gene mutations are linked to Gorlin’s syndrome, which is characterized by basal cell carcinomas, odontogenic cheratocysts, nevus disease, and ovarian fibrosarcomas.26

    Genes Predisposing to Ovarian Cancer

    Defects in the double strand breaks repair system represent approximately 10–15% of hereditary epithelial ovarian cancer.2 The genes involved are moderately penetrant and are associated with a two-fold to four-fold increased risk of developing ovarian cancer38 (Table 1).

    Epigenetic Silencing of BRCA1

    The epigenetic silencing of BRCA1 occurs through promoter hypermethylation. The epithelial ovarian cancers with this feature, according to the Cancer Genome Atlas, unlike BRCA1-2 mutations, appear to be platinum resistant and display a poor prognosis.8 21

    RAD51

    RAD51C is an integral component of the Fanconi anemia/BRCA pathway. Its heterozygous missense mutations are associated with increased risks of breast and ovarian cancer22 36 while homozygous mutations determine a Fanconi anemia phenotype. RAD51C mutations are rare conditions, with the exception of some founder populations. Also, inactivating mutations in RAD51D predispose to ovarian and breast cancer. The risk of ovarian and breast cancers is higher in RAD51C and RAD51D pathogenetic variant carriers, but the risks vary by family history of cancer. The incidence of epithelial ovarian cancers increases to a peak at about 58–60 years of age.39

    In particular, the estimate ovarian cancer cumulative lifetime risk is 11% by age 80 for RAD51C and 13% for RAD51D pathogenic variant carriers.39 39 Germline RAD51D mutations are identified in approximately 0.8% of patients with sporadic epithelial ovarian cancers.14 40 According to the NCCN and the European Society for Medical Oncology guidelines, the risk reducing salpingo-oophorectomy should be considered at 45–50 years of age or earlier based on a specific family history of an earlier onset of ovarian cancer, even if the current evidence is not sufficient to make a strict recommendation as to the optimal age.27 28

    CHEK2

    The gene CHEK2 is associated with the Fanconi anemia/BRCA pathway and is located on chromosome 22. Missense mutation of CHEK2 I157T may be correlated with ovarian cystadenomas, borderline ovarian tumors, and low grade invasive cancers but not high grade ovarian cancer41 Currently, there are no specific recommendations about risk reducing salpingo-oophorectomy or routine surveillance.28

    BARD1

    Germline mutations in BARD1 could be related to hereditary susceptibility to breast and ovarian cancer4 but a recent study has not confirmed this.33 There is no evidence for risk reducing salpingo-oophorectomy.28

    ATM

    ATM mutations may increase the risk of breast cancer: the cumulative lifetime risk is 6% by age 50 years and 33% by age 80 years. Large studies show a moderately increased risk for ovarian cancer. According to the NCCN guidelines, patients with ATM mutations should be counseled, based on family history, about risk reducing salpingo-oophorectomy.28

    ATR

    ATR inhibitions interrupt the function of homologous recombination repair and could contribute to a homologous recombination deficiency profile.21 There are no recommendations available about risk reducing salpingo-oophorectomy.

    EMSY

    The germline amplification of EMSY could contribute to the homologous recombination deficiency profile.21 There are no recommendations available about risk reducing salpingo-oophorectomy.

    BRIP1

    BRIP1 is a Fanconi anemia gene; its inactivating truncating mutations could be associated with an increased risk of breast (approximately two-fold)33 and ovarian cancer (relative risk 11.22, 95% confidence interval 3.2 to 34.1). The estimated cumulative lifetime risk of ovarian cancer is approximately 5.8%%.42 Pathogenetic variants in BRIP1 may be detected in up to 0.6–0.9% of ovarian cancers.43 The deleterious germline mutations of BRIP1 are mainly associated with the high grade serous epithelial subtype.42 According to the NCCN and the European Society for Medical Oncology guidelines, risk reducing salpingo-oophorectomy should be offered at around 45–50 years of age or earlier based on a specific family history of an earlier onset of ovarian cancer even if the current evidence is not sufficient to make a strict recommendation as to the optimal age.27 28 Homozygosis mutations on BRIP1 is associated with Fanconi anemia.

    PALB2

    PALB2 biallelic mutations cause Fanconi anemia, an autosomal recessive disease characterized by developmental abnormalities, bone marrow failure, and increased risk of cancers.33 PALB2 is located on chromosome 16 and its heterozygous germline mutations are associated with increased risks of breast, pancreatic, and ovarian cancer.44 PALB2 mutations are rare conditions.42A recent study demonstrated the association between PALPB2 mutations and ovarian cancer, with a relative risk of 2.9; the estimated absolute risk at age 80 years is about 5%.44 According to the NCCN guidelines, patients with PALB2 mutations should be counseled, based on family history, about risk reducing salpingo-oophorectomy.28

    MRN Complex

    Mutations of the MRN complex could increase the risk of ovarian and breast cancers.4 NBS1 (also known as NBN) gene codes for the protein nibrin. Heterozygous NBN mutations are associated with an increased risk of developing breast cancer and, possibly, ovarian cancer.45 According to the NCCN guidelines, due to the potential increased risk in ovarian cancer, patients with an NBS1 mutation should be counseled, based on family history, about risk reducing salpingo-oophorectomy.28

    Ovarian Cancer Risk Reduction Beyond Risk Reducing Salpingo-oophorectomy

    Several studies in a BRCA1-2 population showed that risk reducing bilateral salpingo-oophorectomy significantly decreased cancer specific mortality for ovarian, fallopian tube, peritoneal, and breast cancers.46 In BRCA1-2 carriers, the risk of epithelial ovarian cancer is reduced by 80% and the risk of breast cancer in premenopausal women by 50% after risk reducing salpingo-oophorectomy.28 47 Beyond the risk reducing bilateral salpingo-oophorectomy, different strategies could be useful to reduce the rate of ovarian cancer in high risk populations and may be applied before the age recommendations for prophylactic surgery or to delay surgery. Risk reducing surgery remains the only evidence based method to prevent epithelial ovarian cancer.

    As a result of increasing evidence demonstrating that epithelial ovarian cancer originates from the fallopian tube, and due to increasing epidemiological data demonstrating a lower incidence of epithelial ovarian cancer in women who have undergone tubal ligation or salpingectomy, there is great interest in risk reducing salpingectomy with delayed oophorectomy after menopause in high risk populations. Currently, this cannot be suggested outside of clinical trials.27 46 Preliminary data on two clinical trials were presented at the 2019 Annual Meeting of the Society of Gynecological Oncology: early salpingectomy (tubectomy) with delayedoophorectomy in BRCA1/2 gene mutation carriers (TUBA) study and the women choosing surgical prevention (WISP) study.48 49 It will require long term follow-up to compare oncological outcomes of salpingectomy with delayed oophorectomy versus risk reducing oophorectomy in high risk women.

    Several studied have demonstrated the protective role of oral contraceptives on the development of ovarian cancer, with a risk reducing effect of 40–60%.27 50 Although it has been suggested that the use of contraceptives may increase the risk of breast cancer, this increased risk is not confirmed in BRCA1-2 carriers.28 Currently, there are no data from randomized controlled studies about the use of contraceptives in high risk populations.6

    CA125 and transvaginal ultrasound may be suggested for BRCA mutated women who refuse risk reducing surgery, although the sensitivity is low. It could be proposed every 6 months from the age of 35, or 5–10 years before the age of the youngest case of epithelial ovarian cancer in the family. The women must be informed about its low sensitivity and its lack of ability to detect early stage cancer to influence prognosis.51 52 High risk populations should be encouraged to have a healthy lifestyle with a healthy diet, regular exercise, and maintain normal body mass index. Multiparity and prolonged breastfeeding represent protective factors against epithelial ovarian cancer among high risk populations.53 54

    Conclusion

    As there is increasing data on cancer genetics, identification of high risk patients who might benefit from a cancer predisposition assessment is of paramount importance. In all patients with epithelial ovarian cancer, the American Society of Clinical Oncology Guidelines (2020) recommend germline testing of a multigene panel that should include at least BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PMS2, and PALB2.29 In fact, these DNA repair genes are known to increase both the risk of cancer and platinum sensitivity through the homologous recombination mediated repair pathway. Alteration of these genes might predict responses to new emerging drugs which target DNA repair pathways other than poly(ADP-ribose) polymerase inhibitors.55 Targeting these other genes could also help in overcoming resistance to poly(ADP-ribose) polymerase inhibitors. Finally, the cost and availability of panel testing are comparable with testing for BRCA1 and BRCA2 alone, making this a practical choice. Current guidelines need to be periodically reassessed and more intensive efforts will be necessary to organize specialized centers where patients could have mutational screening and genetic counseling. This should make it possible to develop a more comprehensive database for research and evidence based management.4 As we learn more about the genes involved in the homologous recombination pathway and the clinical significance of their mutation, we may be able to personalize cancer treatment and to better tailor the use of targeted therapy. Moreover, these innovations could improve the detection of high risk families and consequently increase screening and prevention strategies.

    References

    1. ↵
      1. GLOBOCAN
      . International agency for research on cancer 2018. Available: https://gco.iarc.fr/
    2. ↵
      2. Toss A ,
      3. Molinaro E ,
      4. Sammarini M , et al
      . Hereditary ovarian cancers: state of the art. Minerva Med 2019;110:301-319.
    3. ↵
      2. Cortesi L ,
      3. De Matteis E ,
      4. Toss A , et al
      . Evaluation of transvaginal ultrasound plus CA-125 measurement and prophylactic salpingo-oophorectomy in women at different risk levels of ovarian cancer: the Modena Study Group cohort study. Oncology 2017;93:377–86.
      OpenUrl
    4. ↵
      2. Toss A ,
      3. Tomasello C ,
      4. Razzaboni E , et al
      . Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int 2015;2015:1–11.
      OpenUrl
    5. ↵
      2. Norquist BM ,
      3. Harrell MI ,
      4. Brady MF , et al
      . Inherited mutations in women with ovarian carcinoma. JAMA Oncol 2016;2.
    6. ↵
      2. Santana Dos Santos E ,
      3. Lallemand F ,
      4. Petitalot A , et al
      . HRness in Breast and Ovarian Cancers. Int J Mol Sci 2020;21:3850. doi:10.3390/ijms21113850 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32481735
      OpenUrlPubMed
    7. ↵
      2. Owens DK ,
      3. Krist AH ,
      4. Krist AH , et al
      . Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA -Related Cancer. JAMA 2019;322.
    8. ↵
      1. Cancer Genome Atlas Research Network
      . Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609–15.doi:10.1038/nature10166 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21720365
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      2. Manchana T ,
      3. Phoolcharoen N ,
      4. Tantbirojn P
      . BRCA mutation in high grade epithelial ovarian cancers. Gynecol Oncol Rep 2019;29:102–5.
      OpenUrl
    10. ↵
      2. Tonin P ,
      3. Serova O ,
      4. Simard J , et al
      . The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21. Hum Mol Genet 1994;3:1679–82.
      OpenUrlCrossRefPubMed
    11. ↵
      2. Wooster R ,
      3. Neuhausen SL ,
      4. Mangion J , et al
      . Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265:2088–90.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      2. Shu CA ,
      3. Pike MC ,
      4. Jotwani AR , et al
      . Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol 2016;2.doi:10.1001/jamaoncol.2016.1820 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27367496
    13. ↵
      2. Kuchenbaecker KB ,
      3. Hopper JL ,
      4. Barnes DR , et al
      . Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317:2402–16.
      OpenUrlCrossRefPubMed
    14. ↵
      2. Cook SA ,
      3. Tinker AV
      . Parp inhibitors and the evolving landscape of ovarian cancer management: a review. BioDrugs 2019;33:255–73.
      OpenUrl
    15. ↵
      2. Dulaney C ,
      3. Marcrom S ,
      4. Stanley J , et al
      . Poly(ADP-ribose) polymerase activity and inhibition in cancer. Semin Cell Dev Biol 2017;63:144–53.
      OpenUrl
    16. ↵
      2. Caldecott KW
      . Single-Strand break repair and genetic disease. Nat Rev Genet 2008;9:619–31.
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      2. Taylor KN ,
      3. Eskander RN
      . Parp inhibitors in epithelial ovarian cancer. Recent Pat Anticancer Drug Discov 2018;13:145–58.
      OpenUrlPubMed
    18. ↵
      2. Ring KL ,
      3. Garcia C ,
      4. Thomas MH , et al
      . Current and future role of genetic screening in gynecologic malignancies. Am J Obstet Gynecol 2017;217:512–21.
      OpenUrlCrossRef
    19. ↵
      2. Ledermann JA ,
      3. Drew Y ,
      4. Kristeleit RS
      . Homologous recombination deficiency and ovarian cancer. Eur J Cancer 2016;60:49–58.
      OpenUrl
    20. ↵
      2. Nero C ,
      3. Ciccarone F ,
      4. Pietragalla A , et al
      . Pten and gynecological cancers. Cancers 2019;11.pmid:http://www.ncbi.nlm.nih.gov/pubmed/31569439 doi:10.3390/cancers11101458
    21. ↵
      2. Jiang X ,
      3. Li X ,
      4. Li W , et al
      . Parp inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 2019;23:2303–13.
      OpenUrl
    22. ↵
      2. Pennington KP ,
      3. Swisher EM
      . Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol 2012;124:347–53.
      OpenUrlCrossRefPubMed
    23. ↵
      2. Amin N ,
      3. Chaabouni N ,
      4. George A
      . Genetic testing for epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 2020;65:125–38.
      OpenUrl
    24. ↵
      2. Constantinou P ,
      3. Tischkowitz M
      . Genetics of gynaecological cancers. Best Pract Res Clin Obstet Gynaecol 2017;42:114–24.
      OpenUrl
    25. ↵
      2. Barrow E ,
      3. Robinson L ,
      4. Alduaij W , et al
      . Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009;75:141–9.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      2. Russo A ,
      3. Calò V ,
      4. Bruno L , et al
      . Hereditary ovarian cancer. Crit Rev Oncol Hematol 2009;69:28–44.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      2. Paluch-Shimon S ,
      3. Cardoso F ,
      4. Sessa C , et al
      . Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening. Ann Oncol 2016;27:v103–10.
      OpenUrlCrossRefPubMed
    28. ↵
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/familial high-risk assessment: breast, ovarian and pancreatic 2020. Available: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
    29. ↵
      2. Konstantinopoulos PA ,
      3. Norquist B ,
      4. Lacchetti C , et al
      . Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol 2020;38:1222–45.
      OpenUrlPubMed
    30. ↵
      2. Howitt BE ,
      3. Strickland KC ,
      4. Sholl LM , et al
      . Clear cell ovarian cancers with microsatellite instability: a unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology 2017;6:e1277308.
    31. ↵
      2. Chung SH ,
      3. Woldenberg N ,
      4. Roth AR , et al
      . BRCA and Beyond: Comprehensive Image-rich Review of Hereditary Breast and Gynecologic Cancer Syndromes. Radiographics 2020;40:306–25.
      OpenUrl
    32. ↵
      2. Ahmed AA ,
      3. Etemadmoghadam D ,
      4. Temple J , et al
      . Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol 2010;221:49–56.
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      2. Economopoulou P ,
      3. Dimitriadis G ,
      4. Psyrri A
      . Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev 2015;41:1–8.
      OpenUrlCrossRefPubMed
    34. ↵
      2. Sorrell AD ,
      3. Espenschied CR ,
      4. Culver JO , et al
      . Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome. Mol Diagn Ther 2013;17:31–47.
      OpenUrlCrossRefPubMed
    35. ↵
      2. Shulman LP
      . Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Obstet Gynecol Clin North Am 2010;37:109–33.
      OpenUrlPubMed
    36. ↵
      2. Hall MJ ,
      3. Obeid EI ,
      4. Schwartz SC , et al
      . Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond. Gynecol Oncol 2016;140:565–74.
      OpenUrlCrossRefPubMed
    37. ↵
      2. Gupta S ,
      3. Provenzale D ,
      4. Llor X , et al
      . NCCN guidelines insights: Genetic/Familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw 2019;17:1032–41.
      OpenUrl
    38. ↵
      2. Zelli V ,
      3. Compagnoni C ,
      4. Cannita K , et al
      . Applications of next generation sequencing to the analysis of familial breast/ovarian cancer. High Throughput 2020;9. doi:doi:10.3390/ht9010001. [Epub ahead of print: 10 Jan 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/31936873
    39. ↵
      2. Yang X ,
      3. Song H ,
      4. Leslie G , et al
      . Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D. J Natl Cancer Inst 2020;42.doi:10.1093/jnci/djaa030
    40. ↵
      2. Wickramanayake A ,
      3. Bernier G ,
      4. Pennil C , et al
      . Corrigendum to: Loss of function germline mutations in RAD51D in women with ovarian carcinoma [Gynecol Oncol 127: 552–555, 2012]. Gynecol Oncol 2014;132:260.
    41. ↵
      2. Szymanska-Pasternak J ,
      3. Szymanska A ,
      4. Medrek K , et al
      . Chek2 variants predispose to benign, borderline and low-grade invasive ovarian tumors. Gynecol Oncol 2006;102:429–31.
      OpenUrlCrossRefPubMed
    42. ↵
      2. Ramus SJ ,
      3. Song H ,
      4. Dicks E , et al
      . Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer I 2015;107.
    43. ↵
      2. Voutsadakis IA
      . Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies. World J Gastroenterol 2020;26:1197–207.
      OpenUrl
    44. ↵
      2. Yang X ,
      3. Leslie G ,
      4. Doroszuk A , et al
      . Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 2020;38:674–85.
      OpenUrl
    45. ↵
      2. Bogdanova N ,
      3. Feshchenko S ,
      4. Schürmann P , et al
      . Nijmegen breakage syndrome mutations and risk of breast cancer. Int J Cancer 2008;122:802–6.
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      2. Bercow AS ,
      3. Eisenhauer EL
      . Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer. J Surg Oncol 2019;120:864–72.
      OpenUrl
    47. ↵
      2. Samadder NJ ,
      3. Giridhar KV ,
      4. Baffy N , et al
      . Hereditary cancer Syndromes—A primer on diagnosis and management. Mayo Clin Proc 2019;94:1084–98.
      OpenUrl
    48. ↵
      2. Steenbeek MP ,
      3. Harmsen MG ,
      4. Hermens RPMG , et al
      . Worry and regret in the prospective multicentre tuba study in mutation carriers. Gynecol Oncol 2019;154:22.
    49. ↵
      2. Lu KH ,
      3. Nebgen DR ,
      4. Norquist B , et al
      . WISP: a prospective, multi-center trial of salpingectomy with delayed oophorectomy versus risk reducing salpingo-oophorectomy in women at increased risk for hereditary ovarian cancer. Gynecol Oncol 2019;154:22.
    50. ↵
      2. Friebel TM ,
      3. Domchek SM ,
      4. Rebbeck TR
      . Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst 2014;106.
    51. ↵
      2. Stirling D ,
      3. Evans DGR ,
      4. Pichert G , et al
      . Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the International Federation of gynecology and obstetrics system. J Clin Oncol 2005;23:5588–96.
      OpenUrlAbstract/FREE Full Text
    52. ↵
      2. Nash Z ,
      3. Menon U
      . Ovarian cancer screening: current status and future directions. Best Pract Res Clin Obstet Gynaecol 2020;65:32–45.
      OpenUrl
    53. ↵
      2. Kotsopoulos J ,
      3. Lubinski J ,
      4. Gronwald J , et al
      . Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Int J Cancer 2015;137:1136–46.
      OpenUrl
    54. ↵
      2. Milne RL ,
      3. Osorio A ,
      4. Ramón y Cajal T , et al
      . Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2010;119:221–32.
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      2. Zamarin D
      . Novel therapeutics: response and resistance in ovarian cancer. International Journal of Gynecologic Cancer 2019;29:s16–21.
      OpenUrl
    56. ↵
      2. Vasen HF ,
      3. Watson P ,
      4. Mecklin JP , et al
      . New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–6.
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      2. Li FP ,
      3. Fraumeni JF ,
      4. Mulvihill JJ , et al
      . A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:5358–420.
      OpenUrlAbstract/FREE Full Text
    58. ↵
      2. Tinat J ,
      3. Bougeard G ,
      4. Baert-Desurmont S , et al
      . 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108–9.
      OpenUrlFREE Full Text
    59. ↵
      2. Adam MP ,
      3. Ardinger HH ,
      4. Pagon RA , et al
      . Array. GeneReviews® 1993.

    Footnotes

    • Twitter @annafagottimd

    • AP and MA contributed equally.

    • Contributors AP and MA contributed to the manuscript equally. AP, MA, CM, and AF conceived the presented idea. AP and MA wrote the manuscript with input from all authors. GS, CM, and AF supervised the findings of this work. All authors discussed the results and contributed to the final manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

    • Competing interests AP worked in the Astrazeneca Medical Department until December 2018.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.