title: Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients.
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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sausen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Vilmos
authors.initials: V
authors.lastname: Adleff
authors.affiliation: Personal Genome Diagnostics Inc., Baltimore, Maryland 21224, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Leary
authors.affiliation: The Translational Genomics Research Institute, Scottsdale, Arizona 85004, USA.|Mayo Clinic Arizona, Scottsdale, Arizona 85054, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Valsamo
authors.initials: V
authors.lastname: Anagnostou
authors.affiliation: Personal Genome Diagnostics Inc., Baltimore, Maryland 21224, USA.
authors.forename: Sonya
authors.initials: S
authors.lastname: Parpart-Li
authors.affiliation: Personal Genome Diagnostics Inc., Baltimore, Maryland 21224, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Murphy
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Kay Li
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Hruban
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Scharpf
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: White
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: School of Medicine and Dentistry, University of Rochester, Rochester, New York, 14642, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: The Translational Genomics Research Institute, Scottsdale, Arizona 85004, USA.|Virginia Piper Cancer Center, Scottsdale Healthcare, Scottsdale, Arizona 85258, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.affiliation: Department of Oncology and Medicine, Herlev Hospital, University of Copenhagen, Copenhagen 2730, Denmark.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Drebin
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
mesh_terms: D014408:Biomarkers, Tumor; D004247:DNA / Q000097:blood; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D023281:Genomics; D006801:Humans; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000235:genetics*; D011237:Predictive Value of Tests; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA