Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes

Stephen N. Thibodeau, Amy J. French, Patrick C. Roche, Julie M. Cunningham, David J. Tester, Noralane M. Lindor, Gabriela Moslein, Sean M. Baker, Robert (Mike) Liskay, Lawrence J. Burgart, Ronald Honchel, Kevin C. Halling

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Abstract

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation-cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.

Original languageEnglish (US)
Pages (from-to)4836-4840
Number of pages5
JournalCancer Research
Volume56
Issue number21
StatePublished - Nov 1 1996

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Microsatellite Instability
DNA Mismatch Repair
Mutation
Genes
Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
Proteins
Immunohistochemistry
Missense Mutation
Paraffin
Colorectal Neoplasms
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Thibodeau, S. N., French, A. J., Roche, P. C., Cunningham, J. M., Tester, D. J., Lindor, N. M., ... Halling, K. C. (1996). Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Research, 56(21), 4836-4840.

Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. / Thibodeau, Stephen N.; French, Amy J.; Roche, Patrick C.; Cunningham, Julie M.; Tester, David J.; Lindor, Noralane M.; Moslein, Gabriela; Baker, Sean M.; Liskay, Robert (Mike); Burgart, Lawrence J.; Honchel, Ronald; Halling, Kevin C.

In: Cancer Research, Vol. 56, No. 21, 01.11.1996, p. 4836-4840.

Research output: Contribution to journalArticle

Thibodeau, SN, French, AJ, Roche, PC, Cunningham, JM, Tester, DJ, Lindor, NM, Moslein, G, Baker, SM, Liskay, RM, Burgart, LJ, Honchel, R & Halling, KC 1996, 'Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes', Cancer Research, vol. 56, no. 21, pp. 4836-4840.
Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Research. 1996 Nov 1;56(21):4836-4840.
Thibodeau, Stephen N. ; French, Amy J. ; Roche, Patrick C. ; Cunningham, Julie M. ; Tester, David J. ; Lindor, Noralane M. ; Moslein, Gabriela ; Baker, Sean M. ; Liskay, Robert (Mike) ; Burgart, Lawrence J. ; Honchel, Ronald ; Halling, Kevin C. / Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. In: Cancer Research. 1996 ; Vol. 56, No. 21. pp. 4836-4840.
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abstract = "To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation-cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.",
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AU - Cunningham, Julie M.

AU - Tester, David J.

AU - Lindor, Noralane M.

AU - Moslein, Gabriela

AU - Baker, Sean M.

AU - Liskay, Robert (Mike)

AU - Burgart, Lawrence J.

AU - Honchel, Ronald

AU - Halling, Kevin C.

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