Abstract
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.
Highlights
Colorectal cancer (CRC) is the second most common form of cancer in Europe, and the Czech Republic has the second highest CRC incidence and mortality among 38 European countries [1]
Distribution of genetic defects in tumours Tumours were scored as APC mutated if they carried at least one clearly deleterious APC mutation
APC mutations are the key player in CRC tumorigenesis
Summary
Colorectal cancer (CRC) is the second most common form of cancer in Europe, and the Czech Republic has the second highest CRC incidence and mortality among 38 European countries [1]. The reasons for this are unknown and can include both genetic and environmental factors. The major autosomal dominant disorders with a high risk of CRC include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), familial adenomatous polyposis (FAP), PeutzJeghers syndrome (PJS) and juvenile polyposis (JP) [3]. The incidence of germline MUTYH mutations in Czech FAP negative sporadic CRC patients is lower compared to other European countries [5,6], and there seems to be no increased incidence of the autosomal dominant forms either
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