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| Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers |
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| Author(s): Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomaki P |
| Source: AMERICAN JOURNAL OF PATHOLOGY Volume: 156 Issue: 5 Pages: 1773-1779 Published: MAY 2000 |
| Times Cited: 148 References: 24 |
| Abstract: Microsatellite instability (MSI) is a hallmark of hereditary nonpolyposis colorectal cancer, and in these patients, results from inherited defects in DNA mismatch repair genes, mostly MSH2 and MLH1. MSI also occurs in 15% of sporadic colorectal cancers, but in these tumors, its basis is less well characterized. We investigated 46 sporadic MSI+ colorectal cancers for changes in MSH2 and MLH1 protein expression, followed by the analysis of somatic mutation, loss of heterozygosity (LOH), and promoter hypermethylation as possible underlying defects. Most cases (36/46, 78%) showed lost or reduced MLH1 expression. Among these, a majority (83%) was associated with MLH1 promoter hypermethylation, whereas the rates of LOH and. somatic mutation of MLH1 were 24% and 13%, respectively. Hypermethylation and LOH were inversely correlated, suggesting that they had alternative functions in the inactivation of MLH1. MSH2 expression was lost in 7/46 (15%), and of these, 2 (29%) showed LOH and/or somatic mutation of MSH2, We conclude that most sporadic MSI+ colorectal cancers have an MLH1-associated etiology and that epigenetic modification is a major mechanism of MI;HI inactivation. Moreover, we found a significantly lower prevalence for MLH1 promoter hypermethylation in hereditary nonpolyposis colorectal cancer tumors with MLH1 germline mutations (12/26, 46%), which might explain some differences that are known to occur in the clinicopathological characteristics and tumorigenic pathways between sporadic and hereditary MSI+ colorectal cancers. |
| Document Type: Article |
| Language: English |
| Reprint Address: Peltomaki, P (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, 690 Med Res Facil,420 W 12th Ave, Columbus, OH 43210 USA |
Addresses:
1. Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Columbus, OH 43210 USA
2. Univ Helsinki, Haartman Inst, Dept Med Genet, Helsinki, Finland
3. Univ Helsinki, Haartman Inst, Dept Pathol, Helsinki, Finland |
| Publisher: AMER SOC INVESTIGATIVE PATHOLOGY, INC, 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA |
| Subject Category: Pathology |
| IDS Number: 312XY |
| ISSN: 0002-9440 |
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