Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.
Publication/Presentation Date
4-9-2015
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.
Volume
6
First Page
6744
Last Page
6744
ISSN
2041-1723
Published In/Presented At
Witkiewicz, A. K., McMillan, E. A., Balaji, U., Baek, G., 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
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
25855536
Department(s)
Administration and Leadership
Document Type
Article