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

SIMPLE SUMMARY: Prevalence and cancer risk estimates derived from the evaluation of affected individuals in the clinic are subject to ascertainment bias. This limitation can be mitigated using a genome-first approach in which genotypic data is analyzed before knowing a patient’s phenotype. Our study aimed to analyze two large cohorts with available exome and phenotype data unselected for a specific diagnosis from a genome-first perspective focusing on six pancreatic cancer predisposition genes. We provide estimates of (1) prevalence of heterozygotes for the general population and for individuals with pancreatic cancer and (2) cancer risk for pancreatic cancer for each gene evaluated. For mutation carriers, we found an elevated risk of pancreatic cancer for most genes evaluated, with variation among genes. This work expands our knowledge of the complex genetics of this cancer and will help identify patients at the highest risk who could benefit from future screening or therapeutic strategies. 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.