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