Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

BackgroundLow penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/].MethodsWe performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations.ResultsWe considered the association with the rs6983267 variant at 8q24 as 'highly credible', reaching genome-wide statistical significance in at least one meta-analysis model. We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations.ConclusionsThe limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions

P53 codon 72 polymorphism and its correlation with the presence of cancer in colon and rectum

The most intensively polymorphic site studied in the p53 gene is the one at codon 72 at exon 4, encoding either arginine (CGC, p53Arg) or proline (CCC, p53Pro). This polymorphism is located in a proline rich region (residues 64-92), which is important for p53 dependent apoptosis and growth suppression, but not for cell cycle arrest. These two polymorphic variants have many different activities including their kinetic profiles in SDS-PAGE, their response in cancer chemotherapy and their apoptotic potential. The p53Arg isoform of the protein is more susceptible to inactivation through the ubiquitin-dependent proteolytic pathway by the E6 protein encoded by the Human Papilloma Virus (HPV), than the p53Pro isoform. There have been many efforts to outline the association of this polymorphism with several neoplasias and many other non - neoplastic diseases, however most of the times, the obtained results were contradictory and inconclusive. Colorectal cancer is the second most common type of neoplasia in the U.S and Europe, with a constantly increasing incidence. In this case-control study, the association of the polymorphism of codon 72 of the p53 tumor suppressor gene and the development of colorectal adenocarcinoma was evaluated in a Caucasian population in Greece. Furthermore, the distribution of the polymorphic variants in the population of sporadic colorectal adenocarcinoma was evaluated, in terms of its association with various clinicopathological characteristics, such as age of diagnosis, survival, colorectal tumor site, Duke’s stage, differentiation and sex. Genomic DNA samples from solid tumors from 93 consecutive sporadic colorectal adenocarcinomas served as the case population and 95 healthy individuals who had no clinical evidence of any neoplastic disorder, served as the control population. Genotyping was made by an allelic-specific PCR reaction. The differences in the allelic distribution of Arg72Pro were found to be statistically significant (between cases and controls) (Fisher’s Exact test, P=0.003). The distribution of the alleles of the Arg72Pro polymorphism, in the population of the 93 adenocarcinomas was: 42/93 (45.16%) for the Arg/Arg genotype, 41/93 (44.08%) for the Arg/Pro and 10/93 (10.75%) for Pro/Pro. For the population of the 95 controls, the distribution was as follows: 21/95 (22.10%) for Arg/Arg, 62/95 (65.26%) for Pro/Pro and 12/95 (12.63%) for Pro/Pro. Statistical analyses with odds ratios and 95% confidence intervals revealed a strong association of the homozygous 72Arg allele with the development of colorectal cancer (χ2=11,212, P=0.001, O.R=2.902, 95% confidence interval (CI) =1.540-5.469, for Arg/Arg vs Arg/Pro and Pro/Pro). In addition to that, when tumor location was accounted for, the Arg/Arg carrier genotypes were associated with an increased incidence of left colon cancer (χ2=5.256, P=0.026, OR=2.975, 95% confidence interval (CI) =1.150-7.699) in the population of adenocarcinomas studied. There was no statistical significant differences observed, at any point, in the distribution of allelic genotypes (P>0.05 for Kruskal-Wallis significance), when parameters like mean age of diagnosis (years), sex, survival, histological growth pattern, tumor differentiation or Duke’s staging or HPV infection were taken into account. The above results suggested that there was a strong association of the p53 Arg72Pro polymorphism and the development of malignancy in the sporadic colorectal adenocarcinomas studied. In fact the homozygous p53Arg patients were almost three times in greater possible association with the development of sporadic colorectal adenocarcinoma. Moreover, the distribution of the p53 Arg72Pro genotypes was found to be greatly dependent on the site of the tumor, with the homozygous p53Arg adenocarcinomas to have almost 3 times greater possibility to have arisen from the left colon than the right colon, for both men and women. This difference also had a significant prognostic value, when stratified for the status (alive-dead) of the homozygous p53Arg patients. In conclusion, our data suggest that the p53Arg72 Pro polymorphism is positively associated with the presence of sporadic colorectal cancer, as far as the population of adenocarcinomas studied and that it could have a significant prognostic value, under certain circumstances. The elucidation of this association has given contradictory results between different scientific groups and this makes obvious the fact that more studies are needed. It is possible that studies including much larger population groups, carefully examined as far as ethnical and geographical origin are concerned, will provide a clearer view for the status of this association. In addition to that, the establishment of a genetic “map” of the different ethnicities and populations in the various geographical regions, as far as the p53Arg72 Pro polymorphism is concerned, could give additional information and result in the better understanding of the level of significance of the association of the polymorphism with malignancy. It is also wise that frequencies could be further confirmed from more than one methodologies, so that mistakes and various misclassifications are avoided