Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Michael T. Barrett, Valsamo Anagnostou, Sonya Parpart-Li, Derek Murphy, Qing Kay Li, Carolyn A. Hruban, Rob Scharpf, James R. White, Peter J. O’Dwyer, Peter J. Allen, James R. Eshleman, Craig B. Thompson, David S. Klimstra, David C. Linehan, Anirban Maitra, Ralph H. Hruban, Luis A. Diaz, Daniel D. Von Hoff, Julia S. Johansen, Jeffrey A. Drebin and Victor E. Velculescu ()
Additional contact information
Mark Sausen: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Jillian Phallen: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Vilmos Adleff: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Siân Jones: Personal Genome Diagnostics Inc.
Rebecca J. Leary: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Michael T. Barrett: The Translational Genomics Research Institute
Valsamo Anagnostou: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Sonya Parpart-Li: Personal Genome Diagnostics Inc.
Derek Murphy: Personal Genome Diagnostics Inc.
Qing Kay Li: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Carolyn A. Hruban: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Rob Scharpf: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
James R. White: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Peter J. O’Dwyer: University of Pennsylvania Perelman School of Medicine
Peter J. Allen: Memorial Sloan Kettering Cancer Center
James R. Eshleman: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Craig B. Thompson: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
David S. Klimstra: Memorial Sloan Kettering Cancer Center
David C. Linehan: School of Medicine and Dentistry, University of Rochester
Anirban Maitra: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Ralph H. Hruban: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Luis A. Diaz: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Daniel D. Von Hoff: The Translational Genomics Research Institute
Julia S. Johansen: Herlev Hospital, University of Copenhagen
Jeffrey A. Drebin: Perelman School of Medicine, University of Pennsylvania
Victor E. Velculescu: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine

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

Abstract: Abstract Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

Date: 2015
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DOI: 10.1038/ncomms8686

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