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

Agnieszka K. Witkiewicz (), Elizabeth A. McMillan, Uthra Balaji, GuemHee Baek, Wan-Chi Lin, John Mansour, Mehri Mollaee, Kay-Uwe Wagner, Prasad Koduru, Adam Yopp, Michael A. Choti, Charles J. Yeo, Peter McCue, Michael A. White and Erik S. Knudsen
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Agnieszka K. Witkiewicz: Simmons Cancer Center, UT Southwestern Medical Center
Elizabeth A. McMillan: UT Southwestern Medical Center
Uthra Balaji: UT Southwestern Medical Center
GuemHee Baek: UT Southwestern Medical Center
Wan-Chi Lin: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center
John Mansour: UT Southwestern Medical Center
Mehri Mollaee: Thomas Jefferson University
Kay-Uwe Wagner: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center
Prasad Koduru: UT Southwestern Medical Center
Adam Yopp: UT Southwestern Medical Center
Michael A. Choti: UT Southwestern Medical Center
Charles J. Yeo: Thomas Jefferson University
Peter McCue: Thomas Jefferson University
Michael A. White: Simmons Cancer Center, UT Southwestern Medical Center
Erik S. Knudsen: Simmons Cancer Center, UT Southwestern Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7744

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