A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population.

BACKGROUND AND AIMS: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T(-13910) polymorphism and colorectal cancer in Finnish, British, and Spanish populations. PATIENTS AND METHODS: A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T(-13910) variant by polymerase chain reaction minisequencing. RESULTS: The C/C(-13910) genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07-1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. CONCLUSION: Low lactase enzyme activity, defined by genotyping of the C/T(-13910) variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.