Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability

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...

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Veröffentlicht in:Genes chromosomes & cancer 2002-03, Vol.33 (3), p.322-325
Hauptverfasser: Yamamoto, Hiroyuki, Min, Yongfen, Itoh, Fumio, Imsumran, Arisa, Horiuchi, Shina, Yoshida, Mio, Iku, Shouhei, Fukushima, Hiroshi, Imai, Kohzoh
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Sprache:eng
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Zusammenfassung: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. © 2002 Wiley‐Liss, Inc.
ISSN:1045-2257
1098-2264
DOI:10.1002/gcc.10010