title: Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators.
abstract: OBJECTIVE
  Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs.
  
  
  METHODS
  We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort.
  
  
  RESULTS
  We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P < .01) or CIMP-negative tumors (2 of 34 [6%]; P < .001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7.
  
  
  CONCLUSIONS
  Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Tahara
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Madireddi
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Judith
authors.initials: J
authors.lastname: Garriga
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Yamano
authors.affiliation: Department of Pathology, Iwate Medical University, Morioka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: mestecio@mdanderson.org.
authors.forename: Marcos R H
authors.initials: MR
authors.lastname: Estécio
mesh_terms: D000236:Adenoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002843:Chromatin; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D004265:DNA Helicases / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D020868:Gene Silencing; D005819:Genetic Markers; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C523331:CHD8 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D014157:Transcription Factors; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CIMP; CRC; Colon Cancer; CpG island methylator phenotype; Gene Silencing; Hypermethylation; Microsatellite Instability; SNP; TCGA; The Cancer Genome Atlas; colorectal carcinoma; single-nucleotide polymorphism