Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.
This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors.
Overall, the prevalence of MSI-H colorectal tumor was 2-3-fold higher, while the defect in the percentage expression of mismatch repair (MMR) genes (hMLH1 and hMSH2) was similar in AA patients compared to the U.S. Caucasian population.
Neoplastic cells within benign and malignant mismatch repair-proficient tumors expressed the protein, but no hMSH2 immunoreactivity was observed in the colorectal tumors of patients with germline hMSH2 mutation.
We demonstrate in one family that a hMLH3 mutation segregated with disease together with a missense mutation in hMSH2, which makes us hypothesize that these mutations work together in an additive manner and result in an elevated risk of colorectal tumors in the family.
Although not statistically significant, these results support further research into (i) whether supplemental vitamin D<sub>3</sub> , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ<sub>1</sub> expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ<sub>1</sub> alone, and TGFα relative to TGFβ<sub>1</sub> in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.
Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors.
The authors evaluated the frequency of the carrier status of three ancestral colorectal neoplasm-associated mutations (APC:I1307K, BLM(Ash), and MSH2*1906G>C) found in the Jewish population among a case series with documented colorectal neoplasms.
Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene.