Mutations and polymorphisms in TP53 gene--an overview on the role in colorectal cancer.

A functionally normal TP53 is essential to protect organisms from developing cancer. Somatic mutations in the gene represent one of the highest recurring perturbations in human tumours, including colorectal cancer (CRC). However, the variegated phenotype of wide spectrum of somatic mutations in TP53 and the complexity of the disease prevent a straight interpretation of the mutational analysis in tumours. In addition to the presence of somatic mutations, polymorphic features of the gene may also contribute to alteration of the normal TP53 functioning and variants, mainly in the form of single nucleotide polymorphisms, can be expected to impact susceptibility to sporadic CRC. In the present study, we reviewed the potential role of alterations in the TP53 gene, both somatic mutations and inherited sequence variations, in predisposition to CRC and in the prognosis and response to therapy. The available data from association studies have mostly shown contradictory outcomes. The majority of the studies were based on limited sample sizes and focussed on a limited number of polymorphisms, with main being the rs1042522 (Arg72Pro). Thus far, there is no possible generalisation of the role of TP53 as also a predictor of therapeutic response and prognosis. The effects of TP53, and its abnormalities, on the response of tumours to cytotoxic drugs, radiation and chemoradiation are complex. However, from studies it is emerging that the inherited genetics of TP53 pathway components could be utilised to further define patient populations in their abilities to induce p53 activity in response to either DNA damaging or p53-targeted therapies.

Genotype and haplotype analysis of TP53 gene and the risk of pancreatic cancer: an association study in the Czech Republic.

Pancreatic carcinoma is the fourth leading cause of cancer-related deaths in the Czech Republic, with only a minimum of patients surviving 5 years. The aetiology and molecular pathogenesis are still weakly understood. TP53 has a fundamental role in cell cycle and apoptosis and is frequently mutated in solid tumours, including pancreatic cancer. Based on the assumption that genetic variation may affect susceptibility to cancer development, the role of TP53 polymorphisms in modulating the risk of pancreatic cancer may be of major importance. We investigated four selected polymorphisms in TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T and rs17884306:G>A) in association with pancreatic cancer risk in a case-control study, including 240 cases and controls (for a total of 1827 individuals) from the Czech Republic. Carriers of the variant C allele of rs1042522 polymorphism were at an increased risk of pancreatic cancer [odds ratio (OR) 1.73; 95% confidence interval (CI) 1.26-2.39; P = 0.001]. Haplotype analysis showed that in comparison with the most common haplotype (A(1)GCG), the A(2)CCG haplotype was associated with an increased risk (OR 1.39; 95% CI 1.02-1.88; P = 0.034) and the A(1)CCG with a reduced risk (OR 0.30; 95% CI 0.12-0.76; P = 0.011) for this cancer. These results reflect previous findings of a recent association study, where haplotypes constructed on the same TP53 variants were associated with colorectal cancer risk [Polakova et al. (2009) Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic. Hum. Mutat., 30, 661-668.]. Genetic variation in TP53 may contribute, alone or in concert with other risk factors, to modify the inherited susceptibility to pancreatic cancer, as well as to other gastrointestinal cancers.

Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic.

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A(2)CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population.

Do polymorphisms and haplotypes of mismatch repair genes modulate risk of sporadic colorectal cancer?

The Czech Republic presents one of the highest incidences of colorectal cancer in the world. We genotyped 10 single nucleotide polymorphisms in five DNA mismatch repair genes in 614 colorectal cancer cases and 614 matched controls from this country. The carriers of T-allele of the hMSH6-556G>T polymorphism were at increased risk of colorectal cancer (OR 1.29; 95% CI 1.02-1.62). The stratification of data showed that risk associated with the polymorphism was confined to rectal cancer (OR 1.42; 95% CI 1.03-1.95). The A-allele of the Ex1-145G>A polymorphism in the hMSH6 gene was associated with a decreased risk of colorectal cancer (OR 0.76; 95% CI 0.60-0.98). The C-allele of the IVS4-101G>C polymorphism in hMSH6 was associated with an increased risk of colon cancer (OR 1.34; 95% CI 1.03-1.74). The carriers of the variant allele for the polymorphism IVS9-1406C>T in hMLH1 exhibited a decreased risk of rectal cancer (OR 0.71; 95% CI 0.51-0.98). We observed a differential distribution of haplotypes based on three hMSH6 polymorphisms (-556G>T-Ex1-145G>A-IVS4-101G>C) in the cases and controls (global P=0.02). The TAG haplotype was associated with a decreased risk of colorectal cancer (OR 0.74; 95% CI 0.59-0.92), whereas the most frequent haplotype GGG was associated with increased risk of rectal cancer (OR 1.32; 95% CI 1.05-1.65). However, multiple hypotheses testing diminishes a statistical significance of above associations. Our data suggest a limited role for the investigated individual variants in mismatch repair genes for the susceptibility to the disease. The haplotypes covering hMSH6 gene may, however, be involved in risk modulation in this population.

DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic.

Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.