mismatch-repair diseases
A cause for genetic instability is the frequent appearance of mismatches on the double helix of DNA. Base-base mismatches and small loops may occur during most of the main mechanism that process DNA, that is, replication, recombination and repair itself.
From bacteria to eukaryotes, there are special enzymatic machineries that correct these mismatches, restoring the original DNA sequence, which are generally called DNA mismatch repair.
Defects on DNA repair in bacteria have long been known as a cause for a mutator phenotype. Thus, such a phenotype would be also expected in human cells, and it could also be related to hereditary cancer.
In fact, one of the most interesting recent findings in the field was the discovery that mutations in mismatch repair genes (such as hMSH2, hMLH1, hPMS1 and hPMS2) are responsible for the hereditary nonpolyposis colorectal cancer (HNPCC), which affects as many as 1 in 200 individuals, and also a subset of sporadic colorectal cancers (Jiricny, 1994; Eshleman and Markowitz, 1995).
Individuals are normally heterozygous for the mismatch genes, but the loss of heterozygosity, that may occur spontaneously, leads to genetic instability, originating tumor cells.
In fact, cells from tumors of HNPCC patients show increased microsatellite instability and are normally defective for DNA mismatch repair.
As for the ATM gene, the availability of the DNA mismatch repair gene sequences will aid the screening of HNPCC families for the most frequent mutated alleles.
Moreover, other types of sporadic cancers are found to be associated with the instability of microsatellite DNA sequences, probably due to a deficient mismatch repair.
By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude.
Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion.
Pathology
in gastric carcinoma
in colonic carcinoma
Defects in the mismatch repair (MMR) genes hMLH1 and hMSH2 have been found in 10% to 20% of sporadic colorectal carcinomas and also many cases of hereditary nonpolyposis colorectal cancer syndrome. Patients with these tumors have an improved prognosis and may show greater sensitivity to chemotherapy.
Mucinous tumors were common in hMLH1 tumors (36.3%) but not in hMSH2 tumors (11.1%). hMLH1 tumors were most likely to be poorly differentiated (70%), which was uncommon with hMSH2 tumors (22.2%). hMSH2 tumors were more likely to be confined to the wall (66.7%) than hMLH1 (20%) or intact tumors (23%). (14576472)
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DNA mismatch repair
References
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Peltomaki P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet. 2001 Apr;10(7):735-40. PMID: 11257106
Simpson AJ, Caballero OL, Pena SD. Microsatellite instability as a tool for the classification of gastric cancer. Trends Mol Med. 2001 Feb;7(2):76-80. PMID: 11286759
Eshleman JR, Markowitz SD. Mismatch repair defects in human carcinogenesis. Hum Mol Genet. 1996;5 Spec No:1489-94. PMID: 8875255