Modifier gene polymorphisms and influence on disease expression in FAP

Abstract

Background: Familial adenomatous polyposis (FAP) is a hereditary autosomal dominant condition characterized by the appearance of hundreds to thousands of adenomatous polyps throughout the colon and rectum. If the condition is left untreated it will ultimately develop into colorectal cancer. Most of the articles available today concerning FAP focus on the adenomatous polyposis coli gene as this gene appears to be the most frequent mutated gene in FAP patients. Recent studies suggest that certain modifier genes may play an important role in the development of colorectal cancer in the general population this may also be true for FAP.

Aim of the study: The aim of this study was to examine 199 Australian APC mutation positive FAP patients with a molecular diagnosis of FAP for polymorphisms in five loci on chromosomes 10p14, 8q23.3, 8q24, 11q23, 18q21 and the gene ATP5a1.

Methods: The genotypes were determined for each individual by finding the polymorphic combination for the candidate single nucleotide polymorphisms (SNPs). When a genotype was determined for a particular DNA sample, the nucleotide present at the polymorpic site was reported. The results were analysed using statistical programs.

Results: The result of this study revealed that there is an increased risk of developing polyps if a patient harbours the heterozygote or variant genotype of the SNP rs10318 compared to patients with the wildtype genotype. This appears to be a protective effect against early polyp development in FAP individuals who harbours the variant genotype of SNP rs3802842 compared with those with a wildtype or heterozygote genotype. Patients harbouring the variant genotype of the SNP rs4779584 have an increased risk of developing polyps and CRC at an earlier stage than patients harbouring a wildtype or heterozygote genotype.

Conclusion: In conclusions the findings from this study indicate that modifier genes have an effect on disease expression in FAP patients. These results warrant further investigation in larger FAP populations that harbour APC mutations to confirm the associations reported herein.