Frequency of Defective DNA Mismatch Repair in Colorectal Cancer among the Alaska Native People
- Lisa A. Boardman1,
- Anne P. Lanier4,
- Amy J. French2,
- Karen V. Schowalter2,
- Lawrence J. Burgart2,
- Kathryn R. Koller4,
- Shannon K. McDonnell3,
- Daniel J. Schaid3 and
- Stephen N. Thibodeau2
- 1Division of Gastroenterology, 2Department of Laboratory Medicine and Pathology, and 3Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota and 4Office of Alaska Native Health Research, Division of Community Health Services, Alaska Native Tribal Health Consortium, Anchorage, Alaska
- Requests for reprints:
Stephen N. Thibodeau, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, 920 Hilton Building, Rochester, MN 55905. Phone: 507-284-4696; Fax: 507-284-0670. E-mail: sthibodeau{at}mayo.edu
Abstract
The frequency of colorectal cancer (CRC) among the Alaska Native people is the highest of any ethnic group in the United States. In this study, CRC from 329 Alaska Native people (165 Eskimo, 111 Indians, and 53 Aleut) were evaluated for evidence of defective DNA mismatch repair (MMR) by testing tumors for altered protein expression (hMLH1, hMSH2, and hMSH6) and for the presence of microsatellite instability. Of the 329 samples tested, 46 (14%) showed both microsatellite instability and altered protein expression; 42 (91%) with a loss of hMLH1, 3 (7%) hMSH2, and 1 (2%) hMLH1/hMSH6. Tumors with loss of hMLH1 were further evaluated for hMLH1 promoter hypermethylation and for the presence of the BRAF-V600E mutation. Among cases tested, all 19 (100%) tumors among the Eskimo patients showed hMLH1 promoter hypermethylation, whereas this was the case for only 3 of the 7 (42%) tumors among the Aleut (P = 0.002) and 5 of the 10 (50%) tumors from the Indians (P = 0.002). The majority of hypermethylated cases (23 of 27) tested positive for the V600E alteration. Of the nine tumors from the Aleut and Indian patients that did not exhibit hMLH1 hypermethylation, eight tested negative for V600E. Overall, the frequency of defective MMR among the three groups was not statistically different (P = 0.75). However, the data suggest that the pathogenesis of CRC may differ between the three groups. The CRC with defective MMR among the Eskimo sample fit the typical profile for hMLH1-related cancer associated with sporadic CRC, whereas the pattern in the Aleut and Indian suggests the possibility that germ line hMLH1 mutations may be present. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2344–50)
Footnotes
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Grant support: USPHS, NIH grant CA68535 and U.S. Department of Health and Human Services, Indian Health Service, Native American Research Center for Health grant U26 9400005.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted September 12, 2007.
- Received June 26, 2007.
- Revision received September 6, 2007.
