PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer (study of pts with both ovarian and breast cancers)

Blogger's Note: the other cancers (KRAS mutations) referred to beyond ovarian and breast cancers include references to lung and melanoma cancers; KRAS mutations have been established in colorectal cancers, however, there are no references on this particular subject within this research article regarding Lynch Syndrome -
an ongoing area of specific research (re: KRAS/Lynch Syndrome/blog posting of May 16, 2012 Jnl ASCP)
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PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer


Table 1. The KRAS-variant is significantly associated with uninformative breast and ovarian cancer patients.
doi:10.1371/journal.pone.0037891.t001

Purpose

A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.

Conclusions

These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.

Introduction 

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-susceptibility syndrome marked by an increased risk of developing both ovarian cancer and breast cancer [1]. Families generally considered as having HBOC syndrome are those with multiple family members that have one of these cancers, especially at young ages, or an individual with a cancer in both organs, a “double primary” patient. While this is a relatively rare presentation, a substantial number of women develop both breast and ovarian primaries over their lifetime. While BRCA1 and BRCA2 are strongly associated with HBOC syndrome [2], a large number of HBOC families and women with double primary cancer do not have detectable genetic mutations (herein referred to as “uninformative” patients).
The chances of identifying a mutation causative for HBOC increase when testing individuals diagnosed with double breast/ovarian primaries [3]–[5]. However, a recent report suggests that the rates of BRCA mutations are not higher in a patient with a double primary without a family history than that for isolated first degree relative pairs with single primaries (14% versus 17% with mutations, respectively) [4]. This supports the importance of family history even in patients with double primary cancers. Although BRCA mutations were found in 49% of double primary patients in this recent analysis, it should be noted that this indicates that over half of double primary patients do not have a known genetic cause for their disease. This is consistent with other reports of these patients [3], [5].............The goal of this study was to determine the association of the KRAS-variant with women with double primary breast and ovarian cancer, to further validate the association of this variant with HBOC families. Findings here support the importance of the KRAS-variant in uninformative HBOC families as well as in predicting the risk of multiple primary cancers in women.......

Association of the KRAS-variant with Multiple Cancers in All Patients

Because the KRAS-variant has been found to be associated with an increased risk for other cancers besides breast and ovarian cancer [11], [15] we tested the hypothesis that the KRAS-variant would predict for an increased risk of developing additional cancers in this double primary cohort, regardless of BRCA mutation status. For 183 of the patients in our study where this information was available, 79.2% (n = 145) had reported just the two cancers (breast and ovarian), 12.0% (n = 22) had two separate primary breast cancers and also ovarian cancer, and 8.7% (n = 16) had cancer in an additional organ outside of the breast and ovary (triple primary).

paywalled: Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples - International Journal of Cancer

Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples - Fekete - 2011 - International Journal of Cancer

Abstract

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of our study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, eight were capable to discriminate histology subtypes, and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then, we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan Real Time Polimerase Chain Reaction (RT-PCR) analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort.

medical news: Hypoxia Could Drive Cancer Growth

Hypoxia Could Drive Cancer Growth

"Low oxygen levels in cells may be a primary cause of uncontrollable tumor growth in some cancers, according to a new University of Georgia study. The authors' findings run counter to widely accepted beliefs that genetic mutations are responsible for cancer growth.......

Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)

Epigenetic modification and cancer: mark or stamp?

Abstract

Hypotheses are built upon data, but data require hypotheses before they can be understood. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop. In this commentary on ‘Promoter hypermethylation patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............

Introduction

In hereditary tumours, the first hit occurs in the germ line, whereas in non-hereditary tumours, the first hit occurs in the cell from which the tumour arises. The second hits are always somatic, and can inactivate the second allele in various different ways. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of genomic DNA.............

continue to read full paper

paywalled: US firm corners exclusive license for RAD51C cancer gene : The Lancet Oncology (breast/ovarian mutation)

US firm corners exclusive license for RAD51C cancer gene : The Lancet Oncology

US firm corners exclusive license for RAD51C cancer gene

Bryant Furlow

 

"Already facing a legal challenge to its BRCA1 and BRCA2 patents, Myriad Genetics (Salt Lake City, UT, USA) has secured an exclusive licence for another breast and ovarian cancer-associated gene, RAD51C , under agreement with the German Consortium for Hereditary Breast and Ovarian Cancers, which will share exclusivity in Germany. RAD51C will be used to test patients' hereditary breast and ovarian cancer risks.

“I think it is unfortunate for both the clinical and research communities”, Jim Evans (University"

open access: Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

ScienceDirect.com - Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

 "....While endometrial cancer diagnosed under the age of 50 is not included in the Revised Bethesda Guideline, evidence suggests that these individuals should be evaluated for Lynch syndrome (Resnick et al., 2009). The patient presented was diagnosed with endometrial cancer at the age of 41 and genetic testing revealed triple heterozygosity for BRCA2, MLH1 and MSH6 mutations."

 Introduction

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant cancer susceptibility syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and less frequently MSH6 and PMS2. MMR mutation carriers are predisposed primarily to colorectal cancer and endometrial cancer, with an increased frequency of stomach, ovary, pancreas, upper urinary tract, brain, small bowel, and skin consistently reported. This hereditary syndrome accounts for approximately 2–3% of colorectal cancers and 1–4% of endometrial cancers in the United States (Lynch and de la Chapelle, 2003). Depending on the MMR gene involved, women with Lynch syndrome can have up to an 80% lifetime risk of developing colorectal cancer, and a 20–60% risk of endometrial cancer.

Germline mutations in BRCA1 or BRCA2 (BRCA1/2) cause hereditary breast ovarian cancer syndrome. Female carriers of BRCA1/2 mutations have excessive risks for both breast and ovarian cancer, with lifetime breast cancer estimates ranging from 45% to 84%, and lifetime ovarian cancer estimates ranging from 11% to 62%, depending upon the population studied. BRCA1/2 kindreds are also noted to have an increased frequency of prostate cancer, and in BRCA2 kindreds, increased frequencies of pancreatic cancer and melanoma are observed. The frequency of BRCA1 or BRCA2 mutations in the general population is estimated to be 1 in 300 to 1 in 800, respectively (King et al., 2003).

While there are kindreds with more than one cancer susceptibility syndrome and/or mutation reported in the literature ( [Thiffault et al., 2004] and [Smith et al., 2008]), they are not often encountered in routine clinical settings........

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.

abstract: Medium-sized deletion in the BRCA1 gene: Limitations of Sanger sequencing and MLPA analyses.

Medium-sized deletion in the BRCA1 gene: Limitations of Sanger sequencing and MLPA analyses

Sanger sequencing and MLPA analyses.
Genet Mol Biol. 2012

Abstract
We describe a family with a history of breast and ovarian cancer in which MLPA analysis of the BRCA1 gene pointed to a deletion including a part of exon 11. Further characterization confirmed a loss of 374 bp in a region completely covered by conventional sequencing which had not revealed the deletion. Because this alteration was only detected serendipitously with an MLPA probe, we calculated the probabilities of detecting medium-sized deletions in large exons by methods including initial PCR amplification. This showed that a considerable fraction of medium-sized deletions are undetectable by currently used standard methods of mutation analyses. We conclude that long, widely overlapping amplicons should be used to minimize the risk of missing medium-sized deletions. Alternatively, large exons could be completely covered by narrow-spaced MLPA probes.

abstract: Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

 Blogger's Note: see recent post for a null finding XRCC/Lynch Syndrome

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.:

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

Am J Hum Genet. 2012 Mar 28;


Abstract

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p<0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

abstract: Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.

Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.:

Hum Mutat. 2012 Mar 27;


Abstract

Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders.

open access - Revie: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine (references to Lynch Syndrome/Familial Melanoma)

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine

pdf file

Genetic variants associated with breast cancer risk for BRCA1 mutations carriers

Genetic variants associated with breast cancer risk for BRCA2 mutations carriers

Patterns of association and tumour characteristics

Genetic modifiers of ovarian cancer risk

Environmental, hormonal and reproductive modifiers of risk

Common alleles and cancer risks for mutation carriers

Future challenges     "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........

Conclusions

As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2 mutation carriers in the population is likely to increase. Therefore, it will be important that all mutation carriers are provided with accurate information on their risk of developing breast and ovarian cancer, so that informed decisions on clinical management are made. Our understanding of factors influencing cancer risk variability in mutation carriers has increased over the last few years and is likely to improve further in the near future. Therefore, we are getting closer to the goal of being able to provide more individualized clinical management. Understanding how cancer risks are modified in BRCA1 and BRCA2 mutation carriers will also provide further insights for studying the biological mechanisms of cancer development in mutation carriers. These may lead to the development of novel therapies and more accurate prediction of breast and ovarian cancer progression in mutation carriers.

Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has provided useful insights in study design, analytical methodology and applications, which could be used for studying modifiers of disease in carriers of other high-risk mutations such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.

 

 

 

 

 

 

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.:

Abstract
Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. .........................We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

Access : Mutation analysis of RAD51D in non-BRCA1|[sol]|2 ovarian and breast cancer families : British Journal of Cancer

Access : Mutation analysis of RAD51D in non-BRCA1|[sol]|2 ovarian and breast cancer families : British Journal of Cancer

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families

Abstract

Background:

Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families.

Methods:

The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions.

Conclusion:

RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

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open access: Correspondence Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: More Trouble With Phenocopies

Correspondence:  Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: More Trouble With Phenocopies

• D. Gareth Evans and
• Anthony Howell

JCO published online on February 27, 2012; DOI:10.1200/JCO.2011.40.8021.

• [PDF]

abstract: KRAS mutations in ovarian low-grade endometrioid adenocarcinoma: association with concurrent endometriosis (study of KRAS/BRAF mutations)

Summary

The association between ovarian endometrioid adenocarcinoma and endometriosis is well established. However, not all endometrioid adenocarcinomas are directly related to endometriosis, and it has been suggested that there may be clinicopathologic differences between endometriosis-positive and endometriosis-negative tumors. Molecular alterations in endometrioid adenocarcinoma include KRAS and BRAF mutations, but the incidence of these abnormalities in previous reports has been highly variable (0%-36% and 0%-24%, respectively).....

Keywords

• Ovary;
• Endometrioid;
• Adenocarcinoma;
• Endometriosis;
• Molecular

abstract: Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2

".......The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome."

open access: PLoS ONE: BRCAness Profile of Sporadic Ovarian Cancer Predicts Disease Recurrence

Background

The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes.

Objective

To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival.

Results

High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03).

Conclusions

Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance.

abstract: DICER1 in ovarian cancers : Nature Genetics (sertoli-leydig/juvenile granulosa/sex-cord stromal tumors) : Nature Publishing Group

Abstract:

"Germline mutations in DICER1 underlie a rare syndrome associated with susceptibility to pleuropulmonary blastoma, cystic nephroma and ovarian sex-cord stromal tumors. David Huntsman, Gregg Morin and colleagues (N. Engl. J. Med., published online 21 December 2011; doi:10.1056/NEJMoa1102903) now show that somatic mutations in DICER1 occur at high frequency in non–epithelial ovarian cancers. The authors performed transcriptome and exome sequencing in two Sertoli-Leydig cell tumors, four juvenile granulosa cell tumors and eight primitive germ cell tumors and identified four missense mutations in DICER1 affecting the metal-binding region of the RNase IIIb domain. They subsequently sequenced the portion of DICER1 encoding this region in 101 additional non-epithelial ovarian tumors and identified somatic mutations in 60% of Sertoli-Leydig cell tumors........ On the basis of these findings, the authors propose that these mutations result in an oncogenic miRNA profile whose pathogenicity may be restricted to specific cell types or developmental settings, thereby accounting for the high prevalence of these mutations in particular tumor types."

Medical News: BRCA Mutations Also Play Good Role in Ovarian Cancer - in Oncology/Hematology, Ovarian Cancer from MedPage Today

Action Points

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• A pooled analysis of 26 observational studies found that five-year survival was significantly improved for invasive epithelial ovarian cancer patients carrying BRCA1 or BRCA2 mutations compared with noncarriers.



• Note that data on treatment differences among the heterogeneous population were not available, there were missing data, and procedures for screening for the mutations differed among the studies.

press release: Novel gene mutations associated with bile duct cancer (a Lynch Syndrome associated cancer)

"...Cancers of the gallbladder and bile duct are diagnosed in 12,000 patients in the U.S. each year, the authors note; but only 10 percent are discovered early enough to allow successful surgical treatment. Chemotherapy is modestly effective, leading to an average survival time of less than one year....."

Hereditary ovarian cancer: Beyond the usual suspects - abstract (Fanconi anemia–BRCA,PARP, RAD51C, RAD51D,BRIP1

Blogger's Note: see post Myriad Genetics  rights/RAD51C

.....With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes........ In addition, identifying inherited mutations in a variety of FA–BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors."

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Highlights

► Newly identified hereditary ovarian cancer genes include RAD51C, RAD51D, and BRIP1.
► Many genes in the Fanconi anemia–BRCA pathway may increase risk of ovarian cancer.
► New genomic technologies make comprehensive genetic assessment feasible.