Abstract
CDKN2A coding region germline variants are associated with pancreatic adenocarcinoma (PC) susceptibility. Recently, we described functional germline 5’UTR CDKN2A variants from melanoma patients affecting the post-transcriptional regulation of p16INK4a mRNA that is dependent, at least in part, on an Internal Ribosome Entry Site (IRES) in the 5’UTR region. Here we describe a 5’UTR c.-201_-198delinsCTTT CDKN2A variant (frequency 0.0028 based on 350 PC patients), which seems to be private to PC, since it has never been found in public databases nor in thousands of melanoma patients tested. Functional analyses confirmed IRES activity of the 5’UTR in BX-PC3 PC cells and revealed a functional impact of the identified variant. Using gene reporter assays we observed reduced translation potential in cells treated with the mTOR inhibitor Torin1, a condition that favors the assessment of IRES activity. At the endogenous gene level we quantified allelic imbalance among polysome-associated mRNAs using a patient-derived cell line heterozygous for the c.-201_-198delinsCTTT. Overall, we conclude that this very rare private variant can be considered a potential mutation, specifically associated with PC. Our data indicate that sequencing of the entire 5'UTR of CDKN2A should be included in routine screening of PC cases with suspected inherited susceptibility.
Highlights
Pancreatic adenocarcinoma (PC) is a fatal cancer, with rapid progression and a high death rate
In this study we performed functional testing of a rare private germline CDKN2A 5’UTR c.201_-198delinsCTTT variant associated with PC which we classified as a potential mutation, after applying a pipeline for functional analysis of 5’UTR variants we recently proposed studying CDKN2A 5’UTR variants in melanoma patients [16,17]
In those studies we identified 17 germline single nucleotide variants (SNV) in the CDKN2A 5’UTR in melanoma patients during routine CDKN2A screening performed in several European countries [16] and found that approximately half of them could potentially impact on p16 INK4a post transcriptional regulation, demonstrating that some of them could disrupt Internal Ribosome Entry Site (IRES) activity and influence the translational activity of p16 INK4a
Summary
Pancreatic adenocarcinoma (PC) is a fatal cancer, with rapid progression and a high death rate. The majority of patients die within a year of diagnosis. One of the best strategies to reduce the mortality of the disease is to improve early diagnosis; it is important to identify individuals at high risk as candidates for surveillance protocols. Familial inheritance is implicated in approximately 10% of PC cases. Genetic predisposition to PC remains largely unexplained, next-generation sequencing has led to the new identification of mutations.
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