Whole genome sequencing identifies rare germline variants enriched in cancer related genes in first degree relatives of familial pancreatic cancer patients

Abstract

First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were overrepresented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.

Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients

“…The hypergeometric test showed very high significance ( p < 1e‐22) for the observed overlaps. Finally, we tested overlaps between the 821 PTV genes with our recently reported 448 PTV genes detected in first‐degree relatives of FPC patients (Tan et al., 2021b). There were a total of 62 overlaps observed leading to an extremely high statistical significance (hypergeometric p < 1e‐22).…”

“…Nonsense and frameshift variants like PTVs and nonsynonymous variants that change the sequence and structure of coding proteins reduce the production of ECM proteins to impair matrix integrity, composition, and assembly due to quantitative ECM defects (Lamandé & Bateman, 2020). In a recent WGS study, we have observed a significant enrichment of the ECM pathway by genes carrying rare nonsynonymous variants in first-degree relatives of FPC patients (Tan et al, 2021b). Moreover, a recent network-based analysis of gene expression data on FPC and sporadic pancreatic cancer patients reported increased activity in extracellular structure and ECM organization (Tan et al, 2020).…”

“…Sequence reads were analyzed and aligned to the human reference genome (hg19) using Illumina DRAGEN Bio‐IT software version 3.7. Variants were annotated using VarSeq version 2.2.1 (Golden Helix, Inc.) (Tan et al., 2021b) with (i) functional consequence in RefSeq gene transcripts, (ii) zygosity, (iii) minor allele frequency (MAF) determined using publicly available variant databases (gnomAD), and (iv) presence in ClinVar.…”

“…From the national cohort of 27 FPC families (Tan et al, 2021a(Tan et al, , 2021b, a total of 83 PDAC cases (38 males, 45 females) were identified. Familial predisposition for FPC was defined as presence of either: (1) Two FDRs with PDAC, with at least one of the cases debuting at age <50 year; or (2) at least three FDRs with PDAC.…”

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers

“…However, recently, some frameshift mutations of BRD3 have been found in GC[ 25 ]. Also, Tan et al [ 26 ] found that BRD3 was among the top six driver genes for familial aggregation of PDAC through whole-genome sequencing. That means unlike BRD2/4, BRD3 may function in GI cancer through a different mechanism.…”