Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer

Michael G. House, Ignacio I. Wistuba, Pedram Argani, MingZhou Guo, Richard D. Schulick, Ralph H Hruban, James G. Herman, Anirban Maitra

Research output: Contribution to journalArticle

Abstract

Background: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. Methods: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. Results: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P = .028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P = .034). Conclusions: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.

Original languageEnglish (US)
Pages (from-to)882-889
Number of pages8
JournalAnnals of Surgical Oncology
Volume10
Issue number8
DOIs
StatePublished - 2003

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Gallbladder Neoplasms
Gallstones
Methylation
Tumor Suppressor Genes
Genes
Neoplasms
Gallbladder
Cholecystitis
Chile
Methyltransferases
Polymerase Chain Reaction

Keywords

  • Cancer
  • Gallbladder
  • Methylation
  • Tumor-suppressor genes

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. / House, Michael G.; Wistuba, Ignacio I.; Argani, Pedram; Guo, MingZhou; Schulick, Richard D.; Hruban, Ralph H; Herman, James G.; Maitra, Anirban.

In: Annals of Surgical Oncology, Vol. 10, No. 8, 2003, p. 882-889.

Research output: Contribution to journalArticle

House, Michael G. ; Wistuba, Ignacio I. ; Argani, Pedram ; Guo, MingZhou ; Schulick, Richard D. ; Hruban, Ralph H ; Herman, James G. ; Maitra, Anirban. / Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. In: Annals of Surgical Oncology. 2003 ; Vol. 10, No. 8. pp. 882-889.
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abstract = "Background: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. Methods: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. Results: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72{\%} of the gallbladder neoplasms, 28{\%} of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56{\%}), p73 (28{\%}), APC (27{\%}), and hMLH1 (14{\%}). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42{\%} of the US cases but in only 14{\%} of the Chilean tumors (P = .028). p73 methylation was common among the Chilean cancers (40{\%}) compared with those from the United States (13{\%}; P = .034). Conclusions: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.",
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T1 - Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer

AU - House, Michael G.

AU - Wistuba, Ignacio I.

AU - Argani, Pedram

AU - Guo, MingZhou

AU - Schulick, Richard D.

AU - Hruban, Ralph H

AU - Herman, James G.

AU - Maitra, Anirban

PY - 2003

Y1 - 2003

N2 - Background: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. Methods: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. Results: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P = .028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P = .034). Conclusions: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.

AB - Background: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. Methods: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. Results: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P = .028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P = .034). Conclusions: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.

KW - Cancer

KW - Gallbladder

KW - Methylation

KW - Tumor-suppressor genes

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