title: Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease.
abstract: Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC.
  
  
  
  We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations.
  
  
  
  We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC.
  
  
  
  In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kelsen
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts; Department of Pathology and Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Heins
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Yuting
authors.initials: Y
authors.lastname: He
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanford
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, New York.
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address: kelsend@mskcc.org.
authors.forename: David
authors.initials: D
authors.lastname: Kelsen
mesh_terms: D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000150:complications* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D003424:Crohn Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D016259:Genes, myc / Q000235:genetics; D023281:Genomics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Bowel Cancer; Cancer of the Ileum; IBD; Inflammatory Bowel Disease