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HMSH6 alterations in patients with microsatellite instability-low colorectal cancer.
Cancer Res. 2000 Apr 15; 60(8):2225-31.CR

Abstract

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.

Authors+Show Affiliations

Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10786688

Citation

Parc, Y R., et al. "HMSH6 Alterations in Patients With Microsatellite Instability-low Colorectal Cancer." Cancer Research, vol. 60, no. 8, 2000, pp. 2225-31.
Parc YR, Halling KC, Wang L, et al. HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res. 2000;60(8):2225-31.
Parc, Y. R., Halling, K. C., Wang, L., Christensen, E. R., Cunningham, J. M., French, A. J., Burgart, L. J., Price-Troska, T. L., Roche, P. C., & Thibodeau, S. N. (2000). HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Research, 60(8), 2225-31.
Parc YR, et al. HMSH6 Alterations in Patients With Microsatellite Instability-low Colorectal Cancer. Cancer Res. 2000 Apr 15;60(8):2225-31. PubMed PMID: 10786688.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. AU - Parc,Y R, AU - Halling,K C, AU - Wang,L, AU - Christensen,E R, AU - Cunningham,J M, AU - French,A J, AU - Burgart,L J, AU - Price-Troska,T L, AU - Roche,P C, AU - Thibodeau,S N, PY - 2000/4/29/pubmed PY - 2000/5/16/medline PY - 2000/4/29/entrez SP - 2225 EP - 31 JF - Cancer research JO - Cancer Res. VL - 60 IS - 8 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10786688/HMSH6_alterations_in_patients_with_microsatellite_instability_low_colorectal_cancer_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10786688 DB - PRIME DP - Unbound Medicine ER -