hMSH6 Alterations in Patients with Microsatellite Instability-Low Colorectal Cancer
2000
Two microsatellite instability (MSI) phenotypes have been described in
colorectal cancer (CRC): MSI-H (instability at >30% of the loci
examined) and MSI-L (MSI at 1–30% of the loci examined). The MSI-H
phenotype, observed in both hereditary nonpolyposis colon
cancer-associated CRC and approximately 15% of sporadic CRC,
generally results from mutational or epigenetic inactivation of the DNA
mismatch repair (MMR) genes hMSH2 or
hMLH1 . The genetic basis for the MSI-L phenotype,
however, is unknown. Several other proteins, including hMSH3 and hMSH6,
also participate in DNA MMR. Inactivating mutations of
MSH6 in yeast and human tumor cell lines are associated
with an impaired ability to repair single-base mispairs and small
insertion-deletion loops but not large insertion-deletion loops. This
suggests that hMSH6 mutations are more likely to be
associated with a MSI-L phenotype than a MSI-H phenotype in CRC. To
explore this possibility, we screened tumors from 41 patients with
MSI-L CRC for hMSH6 mutations with
conformation-sensitive gel electrophoresis (CSGE) and for hMSH6 protein
expression by immunohistochemistry. Alterations found with CSGE were
confirmed by DNA sequencing of normal and tumor tissue. One somatic
(Asp389Asn) and 15 germ-line changes were found. Of the 15 germ-line
changes, 9 were found in an intron (none involving splice junctions),
and 6 were found in an exon (Gly39Glu, Leu395Val, and 4 silent
alterations). Immunohistochemical staining for hMSH6 performed on 34 of
the 41 tumors revealed strong nuclear hMSH6 expression in all of the
cases. Overall, our results suggest that hMSH6 mutations
do not play a major role in the development of sporadic CRC with a
MSI-L phenotype.
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