The role of MYH and microsatellite instability in the development of sporadic colorectal cancer
The role of MYH and microsatellite instability in the development of sporadic colorectal cancer
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DOI：
10.1038/sj.bjc.6603421
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发表时间：
2006-11-06
影响因子：
8.8
通讯作者：
Ward, R. L.
中科院分区：
文献类型：
--
作者：
Colebatch, A.;Hitchins, M.;Ward, R. L.
MYH中的双等位基因生殖系突变与结直肠肿瘤相关，结直肠肿瘤通过涉及APC体细胞失活的途径发展。在这项研究中，我们调查了澳大利亚散发性结直肠癌队列中常见MYH突变的发生率，MYH癌症的临床病理特征，并确定错配修复和碱基切除修复（BER）的失活是否相互排斥。对872例结直肠癌患者和478例对照者的淋巴细胞DNA进行MYH基因测序。在癌症人群中发现了两种复合杂合子，这些个体的所有三种癌症均显示出显著的上皮内淋巴细胞浸润。在癌症组中总共发现了11个杂合子，在对照组中发现了5个。来自MYH双等位基因种系突变个体的一个肿瘤也表现出MLHI启动子的双等位基因超甲基化导致的微卫星不稳定性（MSI）。虽然MYH相关癌症在散发性结直肠人群中很少见，但这项研究表明，这些肿瘤可以通过染色体或MSI途径发展。BER或错配修复缺陷引起的肿瘤可能具有共同的生物学特征，即促进淋巴细胞浸润。
Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLHI promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.