Transflip mutations produce deletions in pancreatic cancer

Alexis L. Norris, Hirohiko Kamiyama, Alvin Makohon-Moore, Aparna Pallavajjala, Laura A. Morsberger, Kurt Lee, Denise Batista, Christine A. Iacobuzio-Donahue, Ming Tseh Lin, Alison P. Klein, Ralph H. Hruban, Sarah J. Wheelan, James R. Eshleman

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), CDKN2A (P16) and SMAD4 (DPC4), commonly by homozygous deletions (HDs). Using a combination of high density single-nucleotide polymorphism (SNP) microarray and whole genome sequencing (WGS), we fine-mapped novel breakpoints surrounding deletions of CDKN2A and SMAD4 and characterized them by their underlying structural variants (SVs). Only one third of CDKN2A and SMAD4 deletions (6 of 18) were simple interstitial deletions, rather, the majority of deletions were caused by complex rearrangements, specifically, a translocation on one side of the TSG in combination with an inversion on the other side. We designate these as "TransFlip" mutations. Characteristics of TransFlip mutations are: (1) a propensity to target the TSGs CDKN2A and SMAD4 (P<0.005), (2) not present in the germline of the examined samples, (3) non-recurrent breakpoints, (4) relatively small (47 bp to 3.4 kb) inversions, (5) inversions can be either telomeric or centromeric to the TSG, and (6) non-reciprocal, and non-recurrent translocations. TransFlip mutations are novel complex genomic rearrangements with unique breakpoint signatures in pancreatic cancer. We hypothesize that they are a common but poorly understood mechanism of TSG inactivation in human cancer.

Original languageEnglish (US)
Pages (from-to)472-481
Number of pages10
JournalGenes Chromosomes and Cancer
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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