ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer, affecting 3 - 5% of the global population. K-ras protooncogene and TP53 tumour suppressor gene mutations are among the most common genetic alterations detected in advanced colorectal tumours. OBJECTIVE: To investigate the role of K-ras codon 12 and TP53 exons 5 - 9 mutations in late-stage CRC patients. METHODS: Blood samples were collected from 249 CRC patients, of whom 147 presented with advanced carcinoma. K-ras codon 12 mutations were analysed using polymerase chain reaction-restriction fragment length polymorphism, while direct sequencing was used in screening for TP53 exons 5 - 9 mutations. RESULTS: No significant changes were observed in TP53 exons 5 - 9, except for two cases in which nucleotide replacements were observed in the non-coding regions in intron 4 (c.376-19C>T) and intron 9 (c.993+12T>C). Heterozygous mutations in K-ras codon 12 were observed in 79 individuals suffering from advanced CRC (53.7%). Colon and rectal tumours were equally distributed among the heterozygotes, but colon tumours were mostly present in wild-type homozygotes (84.6%). There was also a predominance of Caucasians among heterozygotes and a predominance of Asians among the wild-type homozygotes. CONCLUSION: Analysis of peripheral blood samples of CRC patients suffering from advanced carcinoma has prognostic value only for K-ras codon 12 mutations, and not for TP53 mutations.
ABSTRACT
We have reported previously that a population near the Semipalatinsk nuclear explosion test site had significantly increased minisatellite mutations (MM), suggesting increased germ-line mutation rates from the exposure in 3 generations. We hypothesize that the MM can be used as a surrogate biomarker for functional genetic alterations, e.g. gene mutations and chromosome aberrations. Therefore, we have investigated the influence of polymorphisms in genes on the expression of MM in the same two populations (247 and 172 individuals, for exposed and control, respectively, in 3 generations), and their relationships with radiation exposure. We have chosen the analyses of three polymorphic DNA - repair genes (XRCC1, XRCC1 and XRCC3) and two xenobiotic detoxification genes (GSTT1 and GSTM1). Among the exposed and in comparison with the wild-type gene, the functionally active XRCC1 Arg194Trp was significantly associated with low MM and over-represented in the exposed compared with the control populations. In a similar analysis, the functionally deficient XRCC1 Arg399Glu and XRCC3 Trp241Met were associated with increased and significantly reduced MM, respectively, but these variant genes were under-represented in the exposed population. Both GSTT1 and GSTM1 nulls were significantly associated with increased MM. The former was under-represented but the latter was significantly over-represented in the exposed compared with the control populations. In summary, the data indicate that the expected enzymatic functions of the polymorphic genes are consistent with the MM expression, except the XRCC1 Arg399Glu variant gene. In addition, the variant genes were retained in the three generations in association with their useful function, except for the GSTM1 null. However, the MM frequencies in the exposed were not consistently and significantly higher than those in the control populations, radiation exposure may therefore not have been the only cause for the high MM frequency among the exposed individuals. Since we studied three generations of citizens, the over- and under-representations of variant genes in the exposed population indicate their persistence and elimination, respectively, from the exposed individuals, suggesting their functional influence on survivability. The latter observation also indicates the complexity of gene and environmental interactions, e.g. the GSTM1 null was significantly over-represented in the exposed population.
