Lipton Lara, Halford Sarah E, Johnson Victoria, Novelli Marco R, Jones Angela, Cummings Carole, Barclay Ella, Sieber Oliver, Sadat Amir, Bisgaard Marie-Luise, Hodgson Shirley V, Aaltonen Lauri A, Thomas Huw J W, Tomlinson Ian P M
Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research United Kingdom, London WC2A 3PX, United Kingdom.
Cancer Res. 2003 Nov 15;63(22):7595-9.
Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.
结直肠癌按照特定的遗传途径发展，包括染色体不稳定（CIN+）、微卫星不稳定（MSI+）以及MSI-CIN-途径。我们已经确定了MYH相关性息肉病（MAP）患者的遗传途径，MAP是一种由碱基切除修复（BER）缺陷导致的结直肠腺瘤和癌症综合征。与之前的研究一样，MAP肿瘤中APC基因的G>T突变频率较高，这与BER缺陷一致。我们发现K-ras突变在MAP肿瘤中很常见，所有变化均包括密码子12的第一个鸟嘌呤残基转换为胸腺嘧啶（G12C，GGT>TGT）。我们在密码子599热点或外显子14的其他位置未发现BRAF突变。几乎所有的MAP癌症都是近二倍体（CIN-），且无MSI+。发现了一些p53突变，但这些并非主要是G>T变化。然而，p53过表达很常见。未发现SMAD4或TGFBIIR突变。MAP肿瘤似乎遵循一种独特的遗传途径，兼具CIN和MSI途径的一些特征。BER缺陷很少伴有CIN或MSI。MAP肿瘤中体细胞突变谱既反映了选择作用，也反映了某些鸟嘌呤残基特别容易发生的超突变。
