Frequency of defective DNA mismatch repair in colorectal cancer among the Alaska Native people

Lisa Allyn Boardman, Anne P. Lanier, Amy J. French, Karen V. Schowalter, Lawrence J. Burgart, Kathryn R. Koller, Shannon K. McDonnell, Daniel J Schaid, Stephen N Thibodeau

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2344-2350
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2007

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Inuits
DNA Mismatch Repair
Colorectal Neoplasms
Neoplasms
Microsatellite Instability
Germ-Line Mutation
Alaska Natives
Ethnic Groups
Proteins
Mutation

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Frequency of defective DNA mismatch repair in colorectal cancer among the Alaska Native people. / Boardman, Lisa Allyn; Lanier, Anne P.; French, Amy J.; Schowalter, Karen V.; Burgart, Lawrence J.; Koller, Kathryn R.; McDonnell, Shannon K.; Schaid, Daniel J; Thibodeau, Stephen N.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 16, No. 11, 01.11.2007, p. 2344-2350.

Research output: Contribution to journalArticle

Boardman, Lisa Allyn ; Lanier, Anne P. ; French, Amy J. ; Schowalter, Karen V. ; Burgart, Lawrence J. ; Koller, Kathryn R. ; McDonnell, Shannon K. ; Schaid, Daniel J ; Thibodeau, Stephen N. / Frequency of defective DNA mismatch repair in colorectal cancer among the Alaska Native people. In: Cancer Epidemiology Biomarkers and Prevention. 2007 ; Vol. 16, No. 11. pp. 2344-2350.
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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.",
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AU - Koller, Kathryn R.

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