Promoter methylation profile in gallbladder cancer
- 128 Downloads
Methylation in the promoter region of genes is an important mechanism of inactivation of tumor suppressor genes. Our objective was to analyze the methylation pattern of some of the genes involved in carcinogenesis of the gallbladder, examining the immunohistochemical expression of proteins, clinical features, and patient survival time.
Twenty cases of gallbladder cancer were selected from the frozen tumor bank. The DNA extracted was analyzed by means of a methylation-specific polymerase chain reaction test for the CDKN2A (p16), MLH1, APC, FHIT, and CDH1 (E-cadherin) genes. Morphological and clinical data and follow-up information were obtained.
All cases were in an advanced stage: histologically moderate or poorly differentiated tumors (95%). Methylation of the promoter area of genes was observed in 5%, 20%, 30%, 40%, and 65% of cases, and an altered immunohistochemical pattern (AIP) in 5%, 35%, 21%, 25%, and 66% for the MLH1, CDKN2A, FHIT, APC, and CDH1 genes, respectively. The Kappa concordance index between methylation of the promoter area and AIP for the MLH1 and CDH1 genes was very high (K > 0.75) and substantial for APC (K > 0.45). No correlation was found between survival time and the methylation of the genes studied.
The high frequency of gene methylation (with the exception of MLH1) and the high agreement between AIP and methylation of the gene promoter area for the MLH1, APC, and CDH1 genes suggest that the inactivation of tumor suppressor genes and of the genes related to the control of cellular proliferation through this mechanism is involved in gallbladder carcinogenesis.
Key wordsCDKN2A MLH1 APC CDH1 FHIT immunohistochemical expression methylation gallbladder cancer
Unable to display preview. Download preview PDF.
- 24.Boland, CR, Thibodeau, SN, Hamilton, SR, Sidransky, D, Eshleman, JR, Burt, RW, et al. 1998A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancerCancer Res58524857PubMedGoogle Scholar
- 27.Stanley Hamilton, LA 2000Tumours of the digestive systemIARC PressLyonGoogle Scholar
- 28.The new TNM classification in gastroenterology (1997). Endoscopy 1998;30:643–9Google Scholar
- 32.Yang, B, House, MG, Guo, M, Herman, JG, Clark, DP 2004Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinomaMod Pathol11Google Scholar
- 36.Kohya, N, Miyazaki, K, Matsukura, S, Yakushiji, H, Kitajima, Y, Kitahara, K, et al. 2002Deficient expression of O(6)-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinomaAnn Surg Oncol93719CrossRefPubMedGoogle Scholar