title: Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers.
abstract: OBJECTIVE
  A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors.
  
  
  METHODS
  We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies.
  
  
  RESULTS
  Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD.
  
  
  CONCLUSIONS
  Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Robles
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Chemical Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Traverso
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Florin M
authors.initials: FM
authors.lastname: Selaru
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Maria
authors.initials: M
authors.lastname: Popoli
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Pittman
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xiquan
authors.initials: X
authors.lastname: Ke
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland; Howard Hughes Medical Institute, Chevy Chase, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: bertvog@gmail.com.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: harrisc@mail.nih.gov.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.affiliation: Ludwig Center at Johns Hopkins, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: npapado1@jhmi.edu.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D003424:Crohn Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome; D018628:Gene Dosage; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D010641:Phenotype
chemical_list: D014408:Biomarkers, Tumor
keywords: Crohn’s Disease; Exome; Sequencing; Ulcerative Colitis