CDKN2A coding region germline variants are associated with pancreatic adenocarcinoma (PC) susceptibility. Recently, we described functional germline 5âUTR CDKN2A variants from melanoma patients affecting the post-transcriptional regulation of p16INK4amRNA that is dependent, at least in part, on an Internal Ribosome Entry Site (IRES) in the 5âUTR region. Here we describe a 5âUTR 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 5âUTR 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 5âUTR of CDKN2A should be included in routine screening of PC cases with suspected inherited susceptibility.
|Titolo:||Functional analysis of a CDKN2A 5’UTR germline variant associated with pancreatic cancer development|
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||01.01 - Articolo su rivista|