The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.
The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.
复制标题
DOI：
10.1136/gut.2010.208462
复制
发表时间：
2010-10
期刊：
影响因子：
24.5
通讯作者：
Green RC
中科院分区：
文献类型：
--
作者：
Woods MO;Younghusband HB;Parfrey PS;Gallinger S;McLaughlin J;Dicks E;Stuckless S;Pollett A;Bapat B;Mrkonjic M;de la Chapelle A;Clendenning M;Thibodeau SN;Simms M;Dohey A;Williams P;Robb D;Searle C;Green JS;Green RC
结直肠癌（CRC）是发达国家第二常见的癌症。纽芬兰是加拿大CRC发病率最高的地区，也是世界上报告的家族性CRC发病率最高的地区。为了确定已知CRC易感基因突变的影响以及已知途径对遗传性CRC发展的贡献，研究了来自纽芬兰人口的750名CRC患者（708个不同家庭）的事件队列。对肿瘤进行微卫星不稳定性（MSI）检测，并对错配修复（MMR）基因进行免疫组织化学分析。在指示的情况下，进行MMR基因和APC的DNA测序和多重连接依赖性探针扩增。对所有患者的DNA进行MUTYH突变筛查。还在肿瘤中测试了BRAF变体p.V600E和MLH 1启动子甲基化的存在。4.6%的患者符合阿姆斯特丹标准（AC），另有44.6%的患者符合修订后的Bethesda标准。在732个肿瘤中观察到10.7%（n=78）的MSI高（MSI-H）。在3.6%（n=27）的患者中，CRC归因于与染色体不稳定性或MSI途径相关的6个已知CRC相关基因中的12种不同遗传突变。7例患者（0.9%）携带APC突变或MUTYH双等位基因突变。在20例（2.7%）MMR基因突变的患者中，14例（70%）有两个MSH 2创始人突变之一。28个AC家族中有17个（61%）没有确定遗传原因，其中15个家族符合家族性CRC X型（FCCTX）的标准。创始人突变仅占病例的2.1%，这不足以解释家族性CRC的高发病率。许多被归类为FCCTX的家族可能具有以孟德尔样方式分离的高度渗透突变。这些家庭将是重要的，以确定额外的CRC易感基因座。
Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.
登录
查看更多内容
影响因子：
158.5
作者：
Hampel, H;Frankel, WL;Papadopoulos, N
通讯作者：
Papadopoulos, N
影响因子：
11.5
作者：
Aaltonen, Lauri;Johns, Louise;Houlston, Richard
通讯作者：
Houlston, Richard
影响因子：
3.9
作者：
Clendenning, M;Hampel, H;de la Chapelle, A
通讯作者：
de la Chapelle, A
激素癌和大肠癌风险的家族史：在安大略省进行的一项病例对照研究。
影响因子：
6.4
作者：
Jang JH;Cotterchio M;Gallinger S;Knight JA;Daftary D
通讯作者：
Daftary D
影响因子：
158.5
作者：
Lichtenstein, P;Holm, NV;Hemminki, K
通讯作者：
Hemminki, K