Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
PLoS One. 2011;6(8):e24114. doi: 10.1371/journal.pone.0024114. Epub 2011 Aug 25.
The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in Europe. To evaluate whether sporadic CRCs in Czech patients have specific mutational profiles we analysed somatic genetic changes in known CRC genes (APC, KRAS, TP53, CTNNB1, MUTYH and BRAF, loss of heterozygosity (LOH) at the APC locus, microsatellite instability (MSI), and methylation of the MLH1 promoter) in 103 tumours from 102 individuals. The most frequently mutated gene was APC (68.9% of tumours), followed by KRAS (31.1%), TP53 (27.2%), BRAF (8.7%) and CTNNB1 (1.9%). Heterozygous germline MUTYH mutations in 2 patients were unlikely to contribute to the development of their CRCs. LOH at the APC locus was found in 34.3% of tumours, MSI in 24.3% and MLH1 methylation in 12.7%. Seven tumours (6.9%) were without any changes in the genes tested. The analysis yielded several findings possibly specific for the Czech cohort. Somatic APC mutations did not cluster in the mutation cluster region (MCR). Tumours with MSI but no MLH1 methylation showed earlier onset and more severe mutational profiles compared to MSI tumours with MLH1 methylation. TP53 mutations were predominantly located outside the hot spots, and transitions were underrepresented. Our analysis supports the observation that germline MUTYH mutations are rare in Czech individuals with sporadic CRCs. Our findings suggest the influence of specific ethnic genetic factors and/or lifestyle and dietary habits typical for the Czech population on the development of these cancers.
捷克共和国的结直肠癌（CRC）发病率在欧洲居于前列。为了评估捷克患者的散发性 CRC 是否具有特定的突变特征，我们分析了已知 CRC 基因（APC、KRAS、TP53、CTNNB1、MUTYH 和 BRAF、APC 基因座杂合性丢失（LOH）、微卫星不稳定性（MSI）和 MLH1 启动子甲基化）中的体细胞遗传变化在 102 名个体的 103 个肿瘤中。突变频率最高的基因是 APC（68.9%的肿瘤），其次是 KRAS（31.1%）、TP53（27.2%）、BRAF（8.7%）和 CTNNB1（1.9%）。2 名患者的种系 MUTYH 突变不太可能导致其 CRC 的发生。APC 基因座 LOH 发生于 34.3%的肿瘤，MSI 发生于 24.3%，MLH1 甲基化发生于 12.7%。7 个肿瘤（6.9%）未发生所检测基因的任何改变。分析结果得出了一些可能与捷克队列相关的发现。体细胞 APC 突变未聚类在突变簇区（MCR）。与 MLH1 甲基化的 MSI 肿瘤相比，MSI 但无 MLH1 甲基化的肿瘤发病更早且突变谱更严重。TP53 突变主要位于热点之外，转换较少。我们的分析支持以下观察结果，即在捷克散发 CRC 个体中，种系 MUTYH 突变罕见。我们的研究结果表明，特定的种族遗传因素和/或捷克人群特有的生活方式和饮食习惯可能对这些癌症的发生有影响。
