title: Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability.
abstract: High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair occurs in the majority of hereditary nonpolyposis colorectal cancers (HNPCCs) and in a subset of sporadic malignant tumors. Clinicopathologic and genotypic features of MSI-H colorectal tumors in HNPCC patients and those in sporadic cases are very similar but not identical. Correlation between the MSI phenotype and aberrant DNA methylation has been highlighted recently. A strong association between MSI and CpG island methylation has been well characterized in sporadic colorectal cancers with MSI-H but not in those of hereditary origin. To address the issue, we analyzed hereditary and sporadic colorectal cancers for aberrant DNA methylation of target genes using methylation-specific polymerase chain reaction. DNA methylation of the MLH1, CDKN2A, MGMT, THBS1, RARB, APC, and p14ARF genes was found in 0%, 23%, 10%, 3%, 73%, 53%, and 33% of 30 MSI-H cancers in HNPCC patients and in 80%, 55%, 23%, 23%, 58%, 35%, and 50% of 40 sporadic colorectal cancers with MSI-H, respectively. Cases showing methylation at three or more loci of six genes other than MLH1 were defined as CpG island methylator phenotype-positive (CIMP +), and 23% of HNPCC tumors and 53% of sporadic cancers with MSI-H were CIMP+ (P = 0.018). Differences in the extent of CpG island methylation, coupled with the differential involvement of several genes by methylation, in HNPCC tumors and sporadic MSI-H colorectal cancers may be associated with diverging developmental pathways in hereditary and sporadic cancers despite similar MSI-H phenotypes.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan. h-yama@sapmed.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Min
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Arisa
authors.initials: A
authors.lastname: Imsumran
authors.forename: Shina
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Mio
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shouhei
authors.initials: S
authors.lastname: Iku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D010641:Phenotype