Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

Abstract

Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability ±`severe' vs`mild' ± and the tumorigenic pathway, as re¯ected by the involvement of functionally important genes, may vary according to the underlying gene(s). We de®ned`mild' RER as mono-or tetranucleotide repeat instability in the absence of widespread instability at dinucleotide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6. No mutations were found, suggesting that these genes were not implicated. We then compared colorectal cancers with`mild' RER (n=15), and those with`severe' RER without (n=11) or with (n=22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGFb RII. The combined mutation rates of the above mentioned loci varied signi®cantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed speci®c patterns of involvement; for example, among tumors with`severe' RER, TGFb RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 or MLH1 mutations. Our ®ndings suggest that dierent subcategories exist among unstable tumors, de®ned by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 and MLH1 are likely to explain only a proportion of these cases.

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

“…41 Colorectal carcinomas as well as gastric cancers and endometrial cancers with high MSI were frequently found to have frameshift mutations in the BAX gene. [42][43][44] Mutations in BAX have also been reported in hematopoietic samples with MSI, 45 but this appears to occur less frequently when compared with colorectal carcinoma samples. While resistance to apoptosis has been noted in cell lines with MSI that display BAX frameshift mutations, 45 MSI itself has not been found to be a negative prognostic factor.…”

Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers

“…Although the timing of the present methylation changes in tumorigenesis remains to be determined, these patterns may confer different developmental pathways on MSI(ϩ) and MSI(Ϫ) tumors, depending on the gene targets. In MSI(ϩ) tumors, MLH1 is likely to be among key targets whose inactivation by hypermethylation gives rise to a cascade of mutations in various growth-regulatory genes (38,39), resulting in the proliferation of mismatch repair deficient clone(s). In contrast, inactivation of other genes, such as p16, that may occur by the same epigenetic mechanism in the nonneoplastic mucosa surrounding MSI(Ϫ) tumors may be crucial to the development of these microsatellite-stable tumors.…”

The Role of Microsatellite Instability in Gastric Low- and High-Grade Lymphoma Development

“…All MSI-positive analyses in this work showed only type II mutations with a single slightly size-changed novel allele which is not typical for the RER ϩ phenotype and that can be also detected in RER-negative tumors. 26 Our current search for mutations characteristically associated with the RER ϩ phenotype, [27][28][29][30][31][32] like MSI at the polydeoxyadenine tract of the transforming growth factor-␤ type II receptor gene and polydeoxyguanine tracts of insulin-like growth factor II receptor and BAX genes or the AGC repeat in the coding region of the E2F-4 gene did not reveal any instability at these repeats. Several studies reported close correlation between tumors displaying MSI-H and the absence of protein expression for either MSH2 or MLH1 in colorectal carcinoma.…”