title: Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma.
abstract: OBJECTIVE
  Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease.
  
  
  OBJECTIVE
  To classify PDAC according to distinct mutational processes, and explore their clinical significance.
  
  
  METHODS
  We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens.
  
  
  METHODS
  Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies.
  
  
  RESULTS
  The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens.
  
  
  CONCLUSIONS
  Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
authors: Ashton A
authors: AA
authors: Connor
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Robert E
authors: RE
authors: Denroche
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada.
authors: Gun Ho
authors: GH
authors: Jang
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Lee
authors: L
authors: Timms
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Sangeetha N
authors: SN
authors: Kalimuthu
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Iris
authors: I
authors: Selander
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Treasa
authors: T
authors: McPherson
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Gavin W
authors: GW
authors: Wilson
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Michelle A
authors: MA
authors: Chan-Seng-Yue
authors: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Ivan
authors: I
authors: Borozan
authors: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Vincent
authors: V
authors: Ferretti
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Robert C
authors: RC
authors: Grant
authors: Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Ilinca M
authors: IM
authors: Lungu
authors: University of Liverpool, Liverpool, England.
authors: Eithne
authors: E
authors: Costello
authors: University of Liverpool, Liverpool, England.
authors: William
authors: W
authors: Greenhalf
authors: University of Liverpool, Liverpool, England.
authors: Daniel
authors: D
authors: Palmer
authors: University of Liverpool, Liverpool, England.
authors: Paula
authors: P
authors: Ghaneh
authors: University of Liverpool, Liverpool, England.
authors: John P
authors: JP
authors: Neoptolemos
authors: Heidelberg University Hospital, Heidelberg, Germany.
authors: Markus
authors: M
authors: Buchler
authors: Mayo Clinic, Rochester, Minnesota.
authors: Gloria
authors: G
authors: Petersen
authors: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
authors: Sarah
authors: S
authors: Thayer
authors: University of Nebraska Medical Centre, Omaha, Nebraska.
authors: Michael A
authors: MA
authors: Hollingsworth
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada.
authors: Alana
authors: A
authors: Sherker
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada.
authors: Daniel
authors: D
authors: Durocher
authors: Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors: Neesha
authors: N
authors: Dhani
authors: Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors: David
authors: D
authors: Hedley
authors: Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
authors: Stefano
authors: S
authors: Serra
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
authors: Aaron
authors: A
authors: Pollett
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada.
authors: Michael H A
authors: MHA
authors: Roehrl
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Prashant
authors: P
authors: Bavi
authors: Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: John M S
authors: JMS
authors: Bartlett
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
authors: Sean
authors: S
authors: Cleary
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Julie M
authors: JM
authors: Wilson
authors: Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors: Ludmil B
authors: LB
authors: Alexandrov
authors: Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors: Malcolm
authors: M
authors: Moore
authors: Department of Pathology, University Health Network, Toronto, Ontario, Canada.
authors: Bradly G
authors: BG
authors: Wouters
authors: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: John D
authors: JD
authors: McPherson
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors: Faiyaz
authors: F
authors: Notta
authors: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada.
authors: Lincoln D
authors: LD
authors: Stein
authors: PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
authors: Steven
authors: S
authors: Gallinger
mesh_terms: D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000276:immunology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D053843:DNA Mismatch Repair / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology; D024522:Genes, BRCA2 / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D060908:CTLA-4 Antigen; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D025521:Tumor Suppressor Proteins