title: Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.
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.
authors: 1] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Agnieszka K
authors: AK
authors: Witkiewicz
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Elizabeth A
authors: EA
authors: McMillan
authors: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Uthra
authors: U
authors: Balaji
authors: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: GuemHee
authors: G
authors: Baek
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198, USA.
authors: Wan-Chi
authors: WC
authors: Lin
authors: Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: John
authors: J
authors: Mansour
authors: Department of Pathology, Thomas Jefferson University Philadelphia Pennsylvania 19107, USA.
authors: Mehri
authors: M
authors: Mollaee
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198, USA.
authors: Kay-Uwe
authors: KU
authors: Wagner
authors: Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Prasad
authors: P
authors: Koduru
authors: Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Adam
authors: A
authors: Yopp
authors: Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Michael A
authors: MA
authors: Choti
authors: Department of Surgery, Thomas Jefferson University, Philadelphia Pennsylvania 19107, USA.
authors: Charles J
authors: CJ
authors: Yeo
authors: Department of Pathology, Thomas Jefferson University Philadelphia Pennsylvania 19107, USA.
authors: Peter
authors: P
authors: McCue
authors: 1] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Michael A
authors: MA
authors: White
authors: 1] Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Erik S
authors: ES
authors: Knudsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D024682:BRCA2 Protein / Q000235:genetics; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D056915:DNA Copy Number Variations; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000077484:Vemurafenib; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; D007211:Indoles; C117307:KRAS protein, human; D009687:Nuclear Proteins; C512260:RBM10 protein, human; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; D013449:Sulfonamides; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)