Genes carrying high-penetrance germline mutations may also be associated with cancer
susceptibility through common low-penetrance genetic variants. To increase the knowledge
on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability
of PDAC familial genes was analysed in this study. We conducted a multi-phase study
analysing 7,745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour
a high-penetrance PDAC-associated mutation in at least one published study. To assess
the effect of the SNPs on PDAC risk, a total of 14,666 PDAC cases and 221,897 controls
across five different studies were analysed. The T allele of the rs1412832 polymorphism,
that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association
with increased risk of developing PDAC (OR=1.11, 95%CI=1.07-1.15, P=5.25×10-9 ). CDKN2B-AS1/ANRIL
is a long non-coding RNA, situated in 9p21.3, and regulates many target genes, among
which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations
and deregulation in PDAC. Our results strongly support the role of the genetic variability
of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary
analysis as a tool for discovering new risk loci in complex human diseases. This article
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