House Michael G, Wistuba Ignacio I, Argani Pedram, Guo MingZhou, Schulick Richard D, Hruban Ralph H, Herman James G, Maitra Anirban
Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231-1000, USA.
Ann Surg Oncol. 2003 Oct;10(8):882-9. doi: 10.1245/aso.2003.02.014.
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.
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.
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).
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.
肿瘤抑制基因的异常甲基化与基因功能丧失相关，这可为胆囊炎症期间出现的散发性肿瘤细胞提供选择性生长优势。
从美国和智利的肿瘤库中选取了54例胆囊肿瘤。对每个肿瘤进行甲基化特异性聚合酶链反应，以检测与六种候选肿瘤抑制基因（p16、APC、甲基鸟嘌呤甲基转移酶、hMLH1、视黄酸受体β-2和p73）相关的启动子甲基化，这些基因涉及多种人类癌症类型。
在72%的胆囊肿瘤、28%的慢性胆囊炎病例以及15例正常胆囊对照中的仅1例中检测到六种候选肿瘤抑制基因中任何一种的异常甲基化。胆囊癌中最常发生甲基化的四个基因是p16（56%）、p73（28%）、APC（27%）和hMLH1（14%）。在美国胆囊癌和来自智利的胆囊癌之间发现了基因甲基化的显著差异，在智利，胆囊癌是癌症相关死亡的主要原因之一。APC甲基化在美国病例中占42%，但在智利肿瘤中仅占14%（P = 0.028）。与来自美国的癌症（13%；P = 0.034）相比，p73甲基化在智利癌症中很常见（40%）。
多个肿瘤抑制基因启动子位点的高甲基化可能有助于慢性炎症胆囊内的肿瘤形成和进展。智利和美国胆囊病例之间甲基化模式的明显差异可能表明世界各地这种癌症存在独特的生物学特性。
