HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 2000 Apr 15;60(8):2225-31
Date
04/29/2000Pubmed ID
10786688Scopus ID
2-s2.0-17944383516 (requires institutional sign-in at Scopus site) 81 CitationsAbstract
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.
Author List
Parc YR, Halling KC, Wang L, Christensen ER, Cunningham JM, French AJ, Burgart LJ, Price-Troska TL, Roche PC, Thibodeau SNMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Cell Nucleus
Colorectal Neoplasms
DNA Mutational Analysis
DNA-Binding Proteins
Exons
Family Health
Female
Genetic Testing
Germ-Line Mutation
Humans
Immunohistochemistry
Introns
Male
Middle Aged
Mutation
Phenotype
Polymorphism, Genetic
Trinucleotide Repeat Expansion
