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

Agnieszka K. Witkiewicz, Elizabeth A. McMillan, Uthra Balaji, Guem Hee 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, Erik S. Knudsen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number6744
JournalNature communications
Volume6
DOIs
StatePublished - Apr 10 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Witkiewicz, A. K., McMillan, E. A., Balaji, U., Baek, G. H., Lin, W. C., Mansour, J., Mollaee, M., Wagner, K. U., Koduru, P., Yopp, A., Choti, M. A., Yeo, C. J., McCue, P., White, M. A., & Knudsen, E. S. (2015). Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nature communications, 6, [6744]. https://doi.org/10.1038/ncomms7744