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Nat Commun. 2015 Apr 9;6:6744. doi: 10.1038/ncomms7744.

Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.

Author information

1
1] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198, USA.
5
Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Pathology, Thomas Jefferson University Philadelphia Pennsylvania 19107, USA.
7
Department of Surgery, Thomas Jefferson University, Philadelphia Pennsylvania 19107, USA.
8
1] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.

PMID:
25855536
PMCID:
PMC4403382
DOI:
10.1038/ncomms7744
[Indexed for MEDLINE]
Free PMC Article

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