hMSH6 alterations in patients with microsatellite instability-low colorectal cancer

Citation
Yr. Parc et al., hMSH6 alterations in patients with microsatellite instability-low colorectal cancer, CANCER RES, 60(8), 2000, pp. 2225-2231
Citations number
39
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
60
Issue
8
Year of publication
2000
Pages
2225 - 2231
Database
ISI
SICI code
0008-5472(20000415)60:8<2225:HAIPWM>2.0.ZU;2-G
Abstract
Two microsatellite instability (MSI) phenotypes have been described in colo rectal cancer (CRC): MSI-H (instability at >30% of the loci examined) and M SI-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 inacti vation of the DNA mismatch repair (MMR) genes hMSH2 or hMLH1, The genetic b asis for the MSI-L phenotype, however, is unknown. Several other proteins, including hMSH3 and hMSH6, also participate in DNA MMR. Inactivating mutati ons of MSH6 in yeast and human tumor cell lines are associated with an impa ired ability to repair single-base mispairs and small insertion-deletion lo ops but not large insertion-deletion loops. This suggests that hMSH6 mutati ons are more likely to be associated with a MSI-L phenotype than a MSI-H ph enotype in CRC. To explore this possibility, we screened tumors from 41 pat ients with MSI-L CRC for hMSH6 mutations with conformation-sensitive gel el ectrophoresis (CSGE) and for hMSH6 protein expression by immunohistochemist ry. Alterations found with CSGE were confirmed by DNA sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line changes were fou nd. 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 ca ses. Overall, our results suggest that hMSH6 mutations do not play a major role in the development of sporadic CRC with a MSI-L phenotype.