Sidelnikov Eduard, Bostick Roberd M, Flanders W Dana, Long Qi, Cohen Vaunita L, Dash Chiranjeev, Seabrook March E, Fedirko Veronika
Department of Epidemiology, Emory University, Atlanta, GA 30322, USA.
Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1599-609. doi: 10.1158/1055-9965.EPI-08-0800.
To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those > or =55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential "treatable" biomarker of risk for colorectal neoplasms.
为了描述错配修复基因MutL同源物1（MLH1）在人类正常结肠隐窝中的表达情况，并评估其作为结直肠肿瘤风险潜在生物标志物的表达参数，我们开展了一项基于结肠镜检查的病例对照试点研究（51例病例，154例对照），研究对象为偶发性散发性结直肠腺瘤。采集外观正常的直肠、乙状结肠和升结肠黏膜活检组织，进行MLH1蛋白的免疫组织化学处理，并使用定制的定量图像分析程序进行分析。病例组升结肠中MLH1的表达平均比对照组低49%（P = 0.03），但在直肠和乙状结肠中几乎没有证据表明病例组和对照组存在差异。在病例组和对照组中，升结肠中MLH1的平均表达随年龄增长而降低[年龄≥55岁者分别降低56%（P = 0.02）和25%（P = 0.16）]，且有一级亲属患结直肠癌病史者也降低[分别降低22%（P = 0.56）和34%（P = 0.16）]。在病例组中，而非对照组中，MLH1的平均表达随当前饮酒、规律服用阿司匹林以及钙、维生素D和叶酸总摄入量增加而升高。直肠中几乎没有类似差异的迹象。这些初步数据表明，正常结肠黏膜中MLH1表达降低，至少在升结肠中，可能与偶发性散发性结直肠腺瘤风险增加以及结直肠肿瘤的可改变风险因素有关，从而支持进一步研究MLH1表达作为结直肠肿瘤风险潜在“可治疗”生物标志物的可能性。
