Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior

Michael G. House, Mingzhou Guo, David Thomas Efron, Keith D. Lillemoe, John L Cameron, James E. Syphard, Craig M. Hooker, Susan C. Abraham, Elizabeth A Montgomery, James G. Herman, Malcolm V Brock

Research output: Contribution to journalArticle

Abstract

The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-β, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P=0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P=0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.

Original languageEnglish (US)
Pages (from-to)1004-1014
Number of pages11
JournalJournal of Gastrointestinal Surgery
Volume7
Issue number8
DOIs
StatePublished - Dec 1 2003

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Gastrointestinal Stromal Tumors
Tumor Suppressor Genes
Methylation
Stomach
Cadherins
Neoplasms
Genes
Recurrence
Survival
Epigenomics
Carcinogens
Disease-Free Survival
Carcinogenesis
Polymerase Chain Reaction
Mortality

Keywords

  • GIST
  • Methylation
  • Tumor suppressor genes

ASJC Scopus subject areas

  • Surgery

Cite this

Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. / House, Michael G.; Guo, Mingzhou; Efron, David Thomas; Lillemoe, Keith D.; Cameron, John L; Syphard, James E.; Hooker, Craig M.; Abraham, Susan C.; Montgomery, Elizabeth A; Herman, James G.; Brock, Malcolm V.

In: Journal of Gastrointestinal Surgery, Vol. 7, No. 8, 01.12.2003, p. 1004-1014.

Research output: Contribution to journalArticle

House, Michael G. ; Guo, Mingzhou ; Efron, David Thomas ; Lillemoe, Keith D. ; Cameron, John L ; Syphard, James E. ; Hooker, Craig M. ; Abraham, Susan C. ; Montgomery, Elizabeth A ; Herman, James G. ; Brock, Malcolm V. / Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. In: Journal of Gastrointestinal Surgery. 2003 ; Vol. 7, No. 8. pp. 1004-1014.
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AU - Cameron, John L

AU - Syphard, James E.

AU - Hooker, Craig M.

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AU - Montgomery, Elizabeth A

AU - Herman, James G.

AU - Brock, Malcolm V

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AB - The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-β, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P=0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P=0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.

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