Zuo Chunlai, Zhang Haihong, Spencer Horace J, Vural Emre, Suen James Y, Schichman Steven A, Smoller Bruce R, Kokoska Mimi S, Fan Chun-Yang
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Otolaryngol Head Neck Surg. 2009 Oct;141(4):484-90. doi: 10.1016/j.otohns.2009.07.007.
The study is designed to elucidate the relationship between epigenetic silencing of the hMLH1 (human MutL homologue 1) gene and microsatellite instability (MSI) and the prognostic values of hMLH1 promoter methylation and MSI in head and neck squamous cell carcinoma (HNSCC).
Cross-sectional study.
Tertiary referral center.
A total of 120 cases of HNSCC were analyzed for hMLH1 promoter hypermethylation, protein expression, and MSI by using methylation-specific polymerase chain reaction, immunohistochemical staining, and polymerase chain reaction amplification with the use of 16 fluorescent-labeled microsatellite markers, followed by fragment analysis.
Of 120 HNSCCs, hMLH1 promoter hypermethylation and decreased hMLH1 protein expression were shown in 39 (32.5%) and 22 (18.3%), respectively. hMLH1 promoter hypermethylation was detected in 13 of 52 (25%) normal-appearing squamous mucosa adjacent to invasive carcinoma. MSI was detected in 21 (17.5%) tumors at two or more markers and in 99 (82.5%) tumors with no evidence of MSI or at only one marker. Hypermethylation of the hMLH1 gene is significantly associated with decreased hMLH1 protein expression (P < 0.001). High-frequency MSI was significantly associated with promoter hypermethylation (P = 0.01) but not with decreased protein expression (P = 0.069) of hMLH1 gene. hMLH1 promoter hypermethylation is significantly associated with decreased cause-specific survival for HNSCC patients (P = 0.03).
Promoter hypermethylation of the hMLH1 gene could be detected early in head and neck squamous carcinogenesis and may be associated with increased MSI and poor survival in HNSCC.
本研究旨在阐明hMLH1（人类MutL同源蛋白1）基因的表观遗传沉默与微卫星不稳定性（MSI）之间的关系，以及hMLH1启动子甲基化和MSI在头颈部鳞状细胞癌（HNSCC）中的预后价值。
横断面研究。
三级转诊中心。
采用甲基化特异性聚合酶链反应、免疫组织化学染色以及使用16种荧光标记微卫星标记进行聚合酶链反应扩增并随后进行片段分析，对120例HNSCC病例进行hMLH1启动子高甲基化、蛋白表达和MSI分析。
在120例HNSCC中，hMLH1启动子高甲基化和hMLH1蛋白表达降低分别见于39例（32.5%）和22例（18.3%）。在52例与浸润性癌相邻的外观正常的鳞状黏膜中，有13例（25%）检测到hMLH1启动子高甲基化。在21例（17.5%）肿瘤中检测到两个或更多标记的MSI，在99例（82.5%）肿瘤中未发现MSI证据或仅在一个标记处发现MSI。hMLH1基因的高甲基化与hMLH1蛋白表达降低显著相关（P < 0.001）。高频MSI与hMLH1基因的启动子高甲基化显著相关（P = 0.01），但与hMLH1基因的蛋白表达降低无关（P = 0.069）。hMLH1启动子高甲基化与HNSCC患者的病因特异性生存率降低显著相关（P = 0.03）。
hMLH1基因的启动子高甲基化可在头颈部鳞状细胞癌发生的早期被检测到，并且可能与HNSCC中MSI增加和生存率降低相关。
