title: The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.
abstract: OBJECTIVE
  The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP.
  
  
  METHODS
  We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing.
  
  
  RESULTS
  We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001).
  
  
  CONCLUSIONS
  The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine and Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA. ajayg@baylorhealth.edu
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Christian N
authors.initials: CN
authors.lastname: Arnold
authors.forename: Toru
authors.initials: T
authors.lastname: Inoue
authors.forename: Cody
authors.initials: C
authors.lastname: Hamilton
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: Carolyn
authors.initials: C
authors.lastname: Compton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Richard
authors.initials: R
authors.lastname: Goldberg
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf