title: Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.
abstract: OBJECTIVE
  Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation.
  
  
  METHODS
  We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays.
  
  
  RESULTS
  We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions.
  
  
  CONCLUSIONS
  Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.
authors.affiliation: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: luoyx25@mail.sysu.edu.cn.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Chao-Jen
authors.initials: CJ
authors.lastname: Wong
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaz
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Slavomir
authors.initials: S
authors.lastname: Dzieciatkowski
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Carter
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Shelli M
authors.initials: SM
authors.lastname: Morris
authors.affiliation: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Medical Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, Ohio.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany GDR.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio.
authors.forename: James D
authors.initials: JD
authors.lastname: Lutterbaugh
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Shrubsole
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address: wgrady@fhcrc.org.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Colon Cancer; Epigenetic Modifications; Gene Regulation; Progression