Investigating prognostic and predictive influences of germline polymorphisms on colorectal adenoma recurrence


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Richard Hubner1, Kenneth Muir2, Jo-Fen Liu2, Richard Logan2, Richard Houlston1

1Insititute of Cancer Research, Surrey, UK, 2University of Nottingham Medical School, Nottingham, UK

Abstract

Investigating prognostic and predictive influences of germline polymorphisms on colorectal adenoma recurrence

Over 90% of colorectal cancers (CRCs) develop from colorectal adenomas (CRAs) via the adenoma-carcinoma sequence. Although resection of CRAs detected at colonoscopy reduces CRC risk 10-40% of individuals will develop recurrent adenoma within 3 years. Prevention of CRA recurrence is thus an important strategy in avoiding CRC development, and is considered the only valid surrogate marker of CRC incidence for the testing of potential chemopreventive agents.

Regular aspirin or folate intake is associated with a reduced risk of CRC and both these agents have been tested in the setting of randomised controlled trials of CRA recurrence prevention. Neither is routinely recommended for chemoprevention of CRC in normal risk individuals due to potential side effects or inadequate efficacy. Genetic variants impacting on the function of proteins involved in aspirin or folate metabolism may enhance chemopreventive activity, altering the risk-benefit ratio in individuals with favourable genotypes. Carriers of variant alleles in the uridine glucuronosyltransferase 1A6 gene are at reduced risk of CRA recurrence, whilst individuals with homozygous variant genotype for the ornithine decarboxylase G316A polymorphism exhibit an enhanced response to aspirin in preventing recurrence. Functional polymorphisms in the methylenetetrahydrofolate reductase and methionine synthase reductase genes influence the impact of folate on CRA recurrence.

Germline polymorphisms with prognostic and predictive influcences in CRA recurrence have the potential to be clinically useful markers to identify individuals at increased risk of colorectal neoplasia and those who may derive differential benefit from chemopreventive agents.