Genetic variation in IGF-1 and breast cancer risk in Ashkenazi carriers and noncarriers of BRCA1/2 mutations.

Earlier studies indicate that high circulating levels of insulin-like growth factor-1 (IGF-1) may be associated with premenopausal breast cancer. We studied variations in the IGF-1 gene and the growth hormone (GH1) gene in relation to risk of breast cancer in 667 Ashkenazi Jewish women (321 cases, 346 controls) from a population-based case-control study in Northern Israel, and a clinical series of 331 founder BRCA mutation carriers (161 affected, 170 unaffected). All participants were tested for six polymorphisms in the IGF-1 gene and one GH1 polymorphism. Logistic regression models were used to estimate odds ratios for haplotype-specific and genotype-specific age-adjusted risks. Two common IGF-1 haplotypes (ATTCAC, GAGTGT) were found, when compared with the most prevalent haplotype ATTCGC (32.5%), to be associated with a decreased risk of breast cancer in premenopausal noncarrier women only. Age-adjusted odds ratios were 0.5 (95% confidence interval: 0.28-0.92) for ATTCAC and 0.46 (95% confidence interval: 0.24-0.89) for GAGTGT. The GH1 polymorphism did not influence the risk of breast cancer in our study population. The IGF-1 gene seems to be associated with breast cancer risk in premenopausal Ashkenazi Jewish women who are not carriers of mutations in BRCA1/2 genes.

Recreational physical activity modifies the association between a common GH1 polymorphism and colorectal cancer risk.

UNLABELLED: Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study. METHODS: The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls). RESULTS: No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (P(interaction) = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94). CONCLUSIONS: We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.