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Abstract 4163: Genomic variation in PDAC-predisposing genes identified using the MCW germline exome panel

Recent evidence suggests that genomic variations in cancer predisposition genes are found at higher prevalence in the general population. However, currently, only a handful of genomic variants in these genes are classified as pathogenic with certainty, leaving a significant number classified as variant of unknown significance (VUS) in terms of their potential pathogenicity. Addressing this problem is of significant relevance for improving cancer screening, genetic counseling, and in some cases therapy. Consequently, the GOAL of the current study was to evaluate genomic variations in pancreatic ductal adenocarcinoma (PDAC) predisposition genes from affected patients. We developed and validated the MCW PDAC Germline AmpliSeq Panel, which assessed variation in 53 cancer predisposition genes, including those from hereditary cancers, chronic pancreatitis, DNA damage repair and metabolism. The target DNA panel was amplified and a library was prepared according to the AmpliSeq for Illumina Custom Panel kit. Paired-end, 2x300bp read sequencing was performed at a depth of at least 500X using the MiSeq platform. Variant calling was performed with the Genome Analysis Toolkit (GATK) v3.7 Haplotype Caller. The protein coding effect of genomic variants was annotated using SNPEff and Ensembl canonical transcripts. We annotated variants with their population allele frequency from GnomAD, cancer incidence from COSMIC, and hereditary disease association from ClinVar and HGMD, using the BioR toolkit.A total of 5,658 variants were found in 545 patients representing 4,087 single-nucleotide variants (SNVs) and 1,146 insertion/deletion variants (indels). Among these variants, we found that 483 were seen previously in the COSMIC database, most of which were associated with ‘carcinoma’ primary histology. When considering all variants regardless of their impact, the genes with variants in the highest number of subjects was POLE , followed by APC , BARD1 , BRCA2 , ATM , and PMS2 . APC had the highest number of coding variants across all samples, followed by PMS2 , BRCA1 , ATM , BRCA2 , and BARD1 . Lastly, 18 variants (0.31%) have been previously identified as pathogenic, likely pathogenic, or disease-causing variations for pancreatic cancer, while 231 (4.08%) represented VUS. In summary, ourfindings support the existence of wide genomic variation in PDAC-predisposition genes. Identified variants include some of uncertain significance, which warrant future functional studies to better understand their pathogenic potential. Combined, these results raise the possibility that some VUS may predispose to PDAC. Citation Format: Jenica Abrudan, Susan Tsai, Wendy Demos, Michael T. Zimmermann, Michael Tschannen, Jennifer Geurts, Angela Mathison, Gwen Lomberk, Douglas Evans, Raul Urrutia. Genomic variation in PDAC-predisposing genes identified using the MCW germline exome panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4163.