A population-based study of polymorphisms of the insulin-like growth factor axis and the oesophageal inflammation, metaplasia, adenocarcinoma sequence

Abstract

Introduction: The insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation and survival and has been implicated in the aetiology of many cancers, including obesityrelated cancers. To date, no studies have examined the relationship between this axis and oesophageal adenocarcinoma (OAC) or its precursors. Aims and Methods: We investigated the association of common polymorphisms of the IGF axis with all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence. The genes examined were IGF-1 and IGF-2, IGF-1 receptor (IGF-1R), IGF binding protein 3 (IGFBP3), the growth hormones (GH-1 and GH-2) and GH receptor (GHR). The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is an all-Ireland population-based, case-control study of OAC and its precursors. We analysed DNA from subjects with reflux oesophagitis (RO, n = 230), Barrett's oesophagus (BO, ≥3 cm BO at endoscopy with specialised intestinal metaplasia on biopsy, n = 189), OAC (n = 207) and normal controls (n = 223). Using a gene-based approach common single-nucleotide polymorphisms (SNP) were identified for each gene using a variety of publicly available online resources. Genotyping was performed using the Sequenom MassARRAY genotyping system and Taqman assay. Results were analysed using Haploview, a software package that provides computation of linkage disequilibrium statistics (including permutation testing) and population haplotype patterns from primary genotype data. 90 IGF axis SNP (tagging 299 alleles) met the inclusion criteria and were analysed. Three polymorphisms were associated with disease status. Results: The IGF-1 SNP rs6214 was associated with BO (p=0.005), even after multiple testing (10 000 permutations; p=0.0389). Using AA genotype as a reference, the odds ratio (OR) for GG (“wild-type”) and BO was 2.40 (95% CI 1.31 to 4.41). The GHR SNP rs6898743 was associated with OAC, p=0.0012 (10 000 permutations; p=0.0112). With GG as the reference, the OR for CC (“wild-type”) genotype and OAC was 0.42 (95% CI 0.23 to 0.76). The IGF-1 (CA)19 “185” repeat was associated with “189” as a reference, the OR for “185” and RO was 7.67 (95% CI 1.73 to 69.92) Conclusion: We systematically examined genetic variations of the IGF axis in a population-based case-control study of OAC, BO and RO. A microsatellite repeat and two SNP were statistically significantly associated with disease states: IGF-1 (CA)19 “185” repeat with RO, rs6214 (IGF-1) with BO and rs6898743 (GHR) with OAC. These SNP could potentially be used as a marker for disease risk, but independent validation of our findings is required. These results also suggest that the IGF pathway may be involved in the development of OAC and its precursors.