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. 2022 Jul 2;14(13):3257.
doi: 10.3390/cancers14133257.

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes

Esteban Astiazaran-Symonds  1 , Jung Kim  1 , Jeremy S Haley  2 , Sun Young Kim  1   3 , H Shanker Rao  2 , Regeneron Genetics Center  4 , David J Carey  2 , Douglas R Stewart  1 , Alisa M Goldstein  1
Affiliations

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes

Esteban Astiazaran-Symonds et al. Cancers (Basel). .

Abstract

Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes.

Keywords: cancer genetics; cancer risk; inherited cancer; pancreatic cancer; pancreatic ductal adenocarcinoma.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Distribution of germline pathogenic variants in ATM identified in participants with pancreatic ductal adenocarcinoma from the UK Biobank and Geisinger MyCode Health Initiative cohorts. Splice site variant (c.8786 + 1G > A) not shown.
Figure 2
Figure 2
Distribution of germline pathogenic variants in BRCA2 identified in participants with pancreatic ductal adenocarcinoma from the UK Biobank and Geisinger MyCode Health Initiative cohorts. Splice site variants (c.7977-1G > C and c.8487 + 1G > C) not shown.
Figure 3
Figure 3
The relative risk of pancreatic ductal adenocarcinoma in participants harboring germline pathogenic variants for each gene. PDAC: pancreatic ductal adenocarcinoma, GPV: germline pathogenic variant. UKB: UK Biobank; GHS: Geisinger MyCode Health Initiative. * Variants identified only in one cohort.
See this image and copyright information in PMC

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