Elsevier

Gynecologic Oncology

Volume 147, Issue 2, November 2017, Pages 375-380
Gynecologic Oncology

Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls

https://doi.org/10.1016/j.ygyno.2017.08.030Get rights and content

Highlights

  • Ovarian cancer risks for mutations in hereditary cancer panel genes were assessed.

  • Mutations by gene from 7768 ovarian cancer cases and reference controls were compared.

  • BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were confirmed as high-risk genes.

  • ATM was identified as a moderate risk ovarian cancer gene.

  • The results will inform clinical management of women with mutations these genes.

Abstract

Objectives

Given the lack of adequate screening modalities, knowledge of ovarian cancer risks for carriers of pathogenic alterations in predisposition genes is important for decisions about risk-reduction by salpingo-oophorectomy. We sought to determine which genes assayed on multi-gene panels are associated with ovarian cancer, the magnitude of the associations, and for which clinically meaningful associations could be ruled out.

Methods

7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory underwent multi-gene panel testing for detection of pathogenic alterations in known or suspected ovarian cancer susceptibility genes. A targeted capture approach was employed to assay each of 19 genes for the presence of pathogenic or likely pathogenic alterations. Mutation frequencies in ovarian cancer cases were compared to mutation frequencies in individuals from the Exome Aggregation Consortium (ExAC). Analyses stratified by family and personal history of other cancers and age at diagnosis were also performed.

Results

Significant associations (p < 0.001) were identified between alterations in 11 genes and ovarian cancer, with eight of these displaying ≥ 5-fold increased risk (BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, RAD51D). Relative risks of ovarian cancer greater than two-fold were also observed for ATM, but could reliably be ruled out for RAD50 and CHEK2.

Conclusions

These results will inform clinical management of women found to carry pathogenic alterations in genes tested on multi-gene panels. The knowledge that some genes are not associated with OC can reduce concerns of women found to carry pathogenic alterations in those genes.

Introduction

Ovarian cancer (OC) is the fifth leading cause of cancer death in U.S. women [1]. Because of the difficulties inherent in pre-symptomatic screening for OC, it is critically important to identify women at high risk of this disease who can be offered risk-reducing salpingo-oophorectomy (RRSO). Genetic screening is an important prevention tool for OC as RRSO in BRCA1 and BRCA2 mutation carriers is proven to reduce mortality [2]. Due to the large hereditary component of OC, multi-gene panel testing is commonly offered to women diagnosed with this form of cancer [3], [4], [5], [6]. Equally important, relatives of women with OC who test negative for a pathogenic alteration can have some measure of assurance of lower personal risk.

Pathogenic mutations in BRCA1 and BRCA2 are found in 10–15% of unselected OC cases and account for up to 40% of heritable OC cases [7], [8], [9], [10], [11]. Several other genes have been associated with OC risk, such as BRIP1, RAD51C, and RAD51D [10], [12], [13], [14], [15], [16]. However, the magnitude of the associations for these OC susceptibility genes is less well defined. In addition, it has been suggested that PALB2 and BARD1 confer increased risk of OC [12], [13], but these findings need further evaluation. OC is also a well-established feature of Lynch syndrome that is associated with pathogenic alterations in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2), but the gene-specific risks for OC with each of the MMR genes are not well defined [6], [12], [17], [18]. Earlier studies of cancer predisposition genes involved in OC have been characterized by small sample sizes, a limited number of genes examined, or both. For example, Ramus et al. analyzed ~ 3200 cases and ~ 3400 controls but only examined four genes (BRIP1, NBN, PALB2, and BARD1) [13]. In contrast, Norquist et al. examined a larger set of genes in 1915 cases and reference controls [12].

In this study, we sought to determine the frequency of pathogenic alterations in a large series of OC cases referred for clinical testing and to provide estimates of OC risk associated with pathogenic alterations in genes commonly tested on multi-gene cancer panels.

Section snippets

Study population

The data analyzed in this study were based on 10,203 adult (age at diagnosis  21) women with OC selected from 140,449 individuals referred to Ambry Genetics (Aliso Viejo, CA) for hereditary cancer multi-gene panel testing between March 15, 2012 and June 30, 2016. Test requisition forms were provided by the ordering clinician and, for the majority of individuals, included details on patient demographics and clinical history including personal and family history of cancer, ages at diagnoses, along

Results

Among the 7768 Caucasian OC cases and the 19 known/suspected OC susceptibility genes, 992 (12.8%) women harbored 1021 P/LP alterations. Twenty-eight (0.36%) women carried more than one P/LP variant. Of the 1021 P/LP alterations observed, 77 were large genomic rearrangements (LGRs), occurring most commonly in BRCA1 (n = 28). For each of the genes evaluated, frequency of P/LP alterations is reported for Caucasian OC cases (Table 2) as well as African American, Asian, Hispanic, and Mixed Ethnicity

Discussion

To our knowledge, this is the largest study to date evaluating the frequency of P/LP alterations in clinical testing panel genes among OC cases. Our primary analyses include 7768 Caucasian OC cases compared to ~ 25,000 controls in the ExAC NFE population. The recent study by Norquist et al., was similar in design as it compared frequencies in a selected series of 1915 patients to ExAC reference controls. However, the Norquist et al. cases were ascertained from a variety of sources, with the

Acknowledgements

This study was supported in part by NIH grants CA92049, CA116167, CA192393, an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation. All authors declare no conflict of interest except for T.P., R.H., H.L., and J.S.D. who declare employment by Ambry Genetics Corp. J.L. and D.E.G. had full access to all the de-identified data in the study and take responsibility for the integrity of the data and the accuracy of the data

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