Transflip mutations produce deletions in pancreatic cancer. Issue 8 (29th May 2015)

• Record Type: Journal Article
• Authors: Norris, Alexis L.; Kamiyama, Hirohiko; Makohon‐Moore, Alvin; Pallavajjala, Aparna; Morsberger, Laura A.; Lee, Kurt; Batista, Denise; Iacobuzio‐Donahue, Christine A.; Lin, Ming‐Tseh; Klein, Alison P.; Hruban, Ralph H.; Wheelan, Sarah J.; Eshleman, James R.
• Is Part Of: Genes, chromosomes & cancer. Volume 54:Issue 8(2015:Aug.)
• Page Start: 472
• Page End: 481
• Publication Date: 2015-05-29
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22258
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), <italic>CDKN2A</italic> (<italic>P16</italic>) and <italic>SMAD4</italic> (<italic>DPC4</italic>), 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 <italic>CDKN2A</italic> and <italic>SMAD4</italic> and characterized them by their underlying structural variants (SVs). Only one third of <italic>CDKN2A</italic> and <italic>SMAD4</italic> 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 <italic>CDKN2A</italic> and <italic>SMAD4</italic> (<italic>P</italic> < 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. © 2015 Wiley Periodicals, Inc.</p> </abstract>