Coggins R P, Cawkwell L, Bell S M, Crockford G P, Quirke P, Finan P J, Bishop D T
Cancer Research UK Genetic Epidemiology Laboratory, St James's University Hospital, Beckett St, Leeds LS9 7TF, UK.
Gut. 2005 May;54(5):636-42. doi: 10.1136/gut.2003.017517.
Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population.
Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression.
hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95-35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37-177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25-19.03)).
Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility.
错配修复（MMR）基因的种系突变会导致胃肠道和女性生殖道癌症风险大幅增加（遗传性非息肉病性结直肠癌（HNPCC））。MMR表达缺失在总体结直肠癌（CRC）中很常见。尽管一部分CRC病例会包括未被识别出MMR突变的个体，但这种缺失被认为主要是后天获得的。本研究探讨CRC人群中MMR基因表达与癌症家族史之间的关联。
从两个特征明确的人群中识别出CRC患者：（1）连续入院的患者（n = 644）和（2）基于人群的病例系列（n = 249）。通过免疫组织化学检测CRC中hMLH1和hMSH2的表达，并使用逻辑回归分析表达与家族史的关系。
在732例CRC中评估了hMLH1和hMSH2的表达，其中8%显示表达缺失。总体而言，未发现hMLH1或hMSH2表达与CRC家族史之间存在关联。结肠外癌症家族史（优势比（OR）5.78（95%置信区间（CI）0.95 - 35.18））和提示HNPCC的家族史（OR 27.84（95% CI 4.37 - 177.56））可预测hMSH2缺失。结肠外癌症家族史或提示HNPCC的家族史不能预测hMLH1缺失，但至少有两个患病亲属的家族史可预测hMLH1缺失（OR 4.88（95% CI 1.25 - 19.03））。
普通人群中hMSH2缺陷型CRC个体表现出提示HNPCC的家族史和其他特征，可能携带种系MMR突变。hMLH1缺失仅与老年时结肠外癌症的强烈家族史相关，提示一种新的易感性机制。
