Dataset Information

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

ABSTRACT: Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) - are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings may help inform the discussion around broader access to BRCA genetic testing.

SUBMITTER: Tennen RI

PROVIDER: S-EPMC7203114 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

Tennen Ruth I RI Laskey Sarah B SB Koelsch Bertram L BL McIntyre Matthew H MH Tung Joyce Y JY

Scientific reports 20200506 1

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) - are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically us ...[more]

PMID: 32376921

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Project description:ImportanceAmong Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.ObjectiveTo determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer.Design, setting, and participantsIn this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017.Main outcomes and measuresGenomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel.ResultsOf the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not.Conclusions and relevanceComprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.

Project description:Abstract Population stratification, or systematic differences in allele frequencies between subpopulations, can distort the results from genome-wide association studies (GWAS). While GWAS are usually conducted within continental (e.g. European) ancestry groups, sub-groups may have specific population histories that result in enrichment for risk or protective alleles for complex disease. In this analysis, we examined genetic risk for glioma in a US population with predominantly Ashkenazi Jewish (AJ) ancestry. Genotyping data were obtained from three prior glioma case-control studies. Best-guess assignment to one of seven subcontinental European ancestry groups was performed using AIPS (https://github.com/biomedicaldatascience/AIPS). Out of a total of 6,416 cases and 7,441 controls across all three studies, 202 cases (3% of all cases, 63% GBM) and 403 controls (5% of all controls) were assigned to the AJ ancestry group. Unconditional logistic regression was performed for by study (adjusted for age and first two principal components) and then studies were combined using fixed effects meta-analysis. No associations reached genome-wide significance (p< 5x10-8), including those detected in prior pan-European GWAS. A nominally significant association was detected on chromosome 17 in ASPA (rs9904040, MAF=20%, p=2.61x10-6, Odds ratio=2.22 [95% confidence interval=1.59–3.09]) which is in linkage equilibrium (r2=0.0013) with the previously detected glioma risk SNP in TP53 (MAF=0.3% in this analysis, p=0.8801) in the European population. In our prior pan-European meta-analysis (Melin et al., 2017, this SNP was non-significant (p=0.0620). This study failed to replicate many previously identified glioma risk alleles, likely due to diminished power due to small sample size. We did identify a novel risk allele on chromosome 17 in ASPA, which encodes for aspartoacylase (which catalyzes deacylation of N-acetyl_L-aspartic acid). Larger sample sizes identified via targeted recruitment are necessary in order to fully characterize genetic risk for glioma in this population, including assessment of rare (MAF< 5%) risk allele associations.

Dataset Information

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

Publications

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

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