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Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.

ABSTRACT: Background:It is often assumed any cancer in a germline BRCA1 or BRCA2 (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals. Methods:We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided. Results:Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls (P?=?1.0x10-10 and P?=?1.4x10-34, respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations (P?=?5.1x10-10 and P?=?3.7x10-9) and cancers without BRCA mutations (P?=?2.8x10-53 and P?=?1.0x10-134). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS (P?=?3.8x10-17 and P?=?1.6x10-8) or benign variants (P?=?1.2x10-28 and P?=?2.2x10-10). There was no difference between individuals with BRCA VUS and those with benign variants. Conclusions:These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.

SUBMITTER: Yost S

PROVIDER: S-EPMC6649772 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.

Yost Shawn S Ruark Elise E Alexandrov Ludmil B LB Rahman Nazneen N

JNCI cancer spectrum 20190419 2

<h4>Background</h4>It is often assumed any cancer in a germline <i>BRCA1</i> or <i>BRCA2</i> (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals.<h4>Methods</h4>We compared the frequency of BRCA mutations, allele lo ...[more]

PMID: 31360904

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Project description:ObjectiveTo describe the testing rate, patient characteristics, temporal trends, timing, and results of germline and somatic BRCA testing in patients with ovarian cancer using real-world data.MethodsWe included a cross-sectional subset of adult patients diagnosed with ovarian cancer between January 1, 2011, and November 30, 2018, who received frontline treatment and were followed for at least 1 year in a real-world database. The primary outcome was receipt of BRCA testing, classified by biosample source as germline (blood or saliva) or somatic (tissue). Lines of therapy (frontline, second line, third line) were derived based on dates of surgery and chemotherapy. Descriptive statistics were analyzed.ResultsAmong 2,557 patients, 72.2% (n=1,846) had at least one documented BRCA test. Among tested patients, 62.5% (n=1,154) had only germline testing, 10.6% (n=197) had only somatic testing, and 19.9% (n=368) had both. Most patients had testing before (9.7%, n=276) or during (48.6%, n=1,521) frontline therapy, with 17.6% (n=273) tested during second-line and 12.7% (n=129) tested during third-line therapy. Patients who received BRCA testing, compared with patients without testing, were younger (mean age 63 years vs 66 years, P <.001) and were more likely to be treated at an academic practice (10.4% vs 7.0%, P =.01), with differences by Eastern Cooperative Oncology Group performance score ( P <.001), stage of disease ( P <.001), histology ( P <.001), geography ( P <.001), and type of frontline therapy ( P <.001), but no differences based on race or ethnicity. The proportion of patients who received BRCA testing within 1 year of diagnosis increased from 24.6% of patients in 2011 to 75.6% of patients in 2018.ConclusionIn a large cohort of patients with ovarian cancer, significant practice disparities existed in testing for actionable BRCA mutations. Despite increased testing over time, many patients did not receive testing, suggesting missed opportunities to identify patients appropriate for targeted therapy and genetic counseling.

Project description:While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging missense variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.

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Dataset Information

Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.

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Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.

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