Jenkins Mark A, Baglietto Laura, Dite Gillian S, Jolley Damien J, Southey Melissa C, Whitty Jonathan, Mead Leeanne J, St John D James B, Macrae Finlay A, Bishop D Timothy, Venter Deon J, Giles Graham G, Hopper John L
Centre for Genetic Epidemiology, The University of Melbourne, 723 Swanston Street, Carlton Victoria 3053, Australia.
Int J Cancer. 2002 Nov 10;102(2):166-71. doi: 10.1002/ijc.10670.
The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer.
我们研究的目的是在排除两个主要错配修复基因种系突变的影响后，研究遗传因素在早发性结直肠癌中的作用。我们对从维多利亚癌症登记处选取的131例首次诊断为原发性结直肠癌时年龄在45岁以下的新发先证者及其一级和二级亲属进行了访谈。对所有12例有家族史且符合遗传性非息肉病性结直肠癌（HNPCC）改良阿姆斯特丹标准的先证者以及其余先证者中随机抽取的31例的种系DNA，通过手工测序筛查hMSH2和hMLH1基因的突变。在131例先证者中有6例（5%）检测到种系突变，均来自“HNPCC”家族。在其余125例先证者中，51例（41%）报告至少有一位一级或二级亲属患有结直肠癌，且一级亲属中结直肠癌患者过多（标准化发病比=2.7，95%可信区间=1.7 - 4.1，p<0.001）。一级亲属到70岁时的终生风险为8.0%（5.0 - 12.8%），而维多利亚人群的风险为3.2%（p = 0.01）。最适合的主基因模型是一种隐性遗传风险，70岁时风险为98%（95%可信区间=24 - 100%），由0.17%的人群携带，可解释45岁前确诊病例中所有结直肠癌的15%。即使排除发现有两个主要错配修复基因之一发生突变的家族，早发性结直肠癌仍具有很强的家族聚集性。有证据表明，存在尚未确定的与结直肠癌高隐性遗传风险相关的基因。
