Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status
Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status
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DOI：
10.1093/hmg/ddh238
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发表时间：
2004-10-01
影响因子：
3.5
通讯作者：
Hofstra, RMW
中科院分区：
文献类型：
--
作者：
Oliveira, C;Westra, JL;Hofstra, RMW
在散发性结直肠肿瘤中，BRAF(V600E)与微卫星不稳定(MSI-H)相关，与KRAS突变负相关。携带hMSH2或hMLH1胚系突变的遗传性非息肉病性结直肠癌(HNPCC)患者的肿瘤不显示BRAF(V600E)，然而关于HNPCC肿瘤中KRAS突变的频率和谱没有一致的数据。我们研究了158例HNPCC肿瘤中的KRAS，这些肿瘤来自胚系hMLH1、hMSH2或hMSH6突变、166例MSI-H和688例微卫星稳定(MSS)散发性癌。所有肿瘤均检测MSI，166例散发性MSI-H结直肠癌(CRC)中81例检测hMLH1启动子高甲基化。在40%的HNPCC肿瘤中发现KRAS突变，突变频率因错配修复基因的不同而不同：hMSH2为48%(29/61)，hMLH1为32%(29/91)，hMSH6为83%(5/6)(P=0.01)。KRAS基因突变频率在HNPCC、MSS和MSI-H癌中差异有统计学意义(P=0.002)，在MSI-H伴hMLH1高甲基化时差异有统计学意义(P=0.005)。此外，HNPCC癌组织中G13D突变频率明显高于MSS(P
In sporadic colorectal tumours the BRAF(V600E) is associated with microsatellite instability (MSI-H) and inversely associated to KRAS mutations. Tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients carrying germline mutations in hMSH2 or hMLH1 do not show BRAF(V600E), however no consistent data exist regarding KRAS mutation frequency and spectrum in HNPCC tumours. We investigated KRAS in 158 HNPCC tumours from patients with germline hMLH1, hMSH2 or hMSH6 mutations, 166 MSI-H and 688 microsatellite stable (MSS) sporadic carcinomas. All tumours were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancer (CRCs) were analysed for hMLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumours, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in hMSH2, 32% (29/91) in hMLH1 and 83% (5/6) in hMSH6 (P=0.01). KRAS mutation frequency was different between HNPCC, MSS and MSI-H CRCs (P=0.002), and MSI-H with hMLH1 hypermethylation (P=0.005). Furthermore, HNPCC CRCs had more G13D mutations than MSS (P