title: Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers.
abstract: Aberrant methylation of 5'gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n = 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Shigematsu
authors.forename: Narayan
authors.initials: N
authors.lastname: Shivapurkar
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Reddy
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nomura
authors.forename: Meena
authors.initials: M
authors.lastname: Augustus
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction