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Transflip mutations produce deletions in pancreatic cancer

Alexis L Norris1, Hirohiko Kamiyama1, Alvin Makohon-Moore1

  • 1Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231.

Genes, Chromosomes & Cancer
|June 3, 2015
PubMed

Insights

Complex genomic rearrangements called "TransFlip" mutations are a common cause of tumor suppressor gene inactivation in pancreatic cancer, driving disease progression. These novel mutations involve translocations and inversions, offering new insights into cancer development.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by the inactivation of tumor suppressor genes (TSGs) like CDKN2A (P16) and SMAD4 (DPC4).
  • Homozygous deletions are a common mechanism for TSG inactivation in PDAC.

Purpose of the Study:

  • To fine-map novel breakpoints surrounding CDKN2A and SMAD4 deletions.
  • To characterize the structural variants (SVs) underlying these deletions.
  • To identify and define a novel complex genomic rearrangement mechanism in pancreatic cancer.

Main Methods:

  • High-density single-nucleotide polymorphism (SNP) microarray analysis.
  • Whole genome sequencing (WGS).
  • Breakpoint mapping and structural variant characterization.

Main Results:

  • The majority of CDKN2A and SMAD4 deletions (12 of 18) were complex rearrangements, not simple deletions.
  • A novel complex rearrangement, termed "TransFlip" mutation, was identified, involving a translocation and an inversion.
  • TransFlip mutations specifically target CDKN2A and SMAD4, are somatic (non-germline), and feature non-recurrent breakpoints and small inversions.

Conclusions:

  • TransFlip mutations represent a novel class of complex genomic rearrangements in pancreatic cancer.
  • These mutations are a significant, yet poorly understood, mechanism for tumor suppressor gene inactivation.
  • Further research into TransFlip mutations may reveal new therapeutic targets for pancreatic cancer.

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