Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk

Abstract

Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/ insulin resistance (IR) traits and signaling pathways, using data from 704 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment–insulin resistance) on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway–related genetic variants) had different associations with CRC risk between strata, and the proportion of the SNP–cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

GASVeM: A New Machine Learning Methodology for Multi-SNP Analysis of GWAS Data Based on Genetic Algorithms and Support Vector Machines

“…It has been reported that the modification in the individual values of plasma insulin levels due to diet may affect the risk of suffering from colorectal cancer [61]. A similar result was found by other researchers in a study performed with a sample of postmenopausal women [62]. Although there are many studies in this line [63,64] and it is known that genetic variants in metabolic signaling pathways may interact with lifestyle factors such as dietary fatty acids influencing colorectal cancer risk, these interrelated pathways are not fully understood [65].…”

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

“…An interesting study by Hu et al [40] indicated that IGF-1 gene expression levels were higher in patients with concomitant MS and CRC than in patients with CRC without MS. In addition, it has been demonstrated that specific single nucleotide polymorphisms (SNPs) of genes within IGF-1/IR traits, in interaction with modifiable lifestyle factors, affect CRC risk in postmenopausal women [55]. Moreover, a possible synergistic effect on CRC risk in postmenopausal women was reported for IR-associated SNPs LINC00460 rs1725459 and MTRR rs722025 in combination with estrogen/oral contraceptive use and smoking [56].…”

Toward fully exploiting the therapeutic potential of marketed pharmaceuticals: the use of octreotide and chloroquine in oncology

“…Given the well-established role of IGF132 and the role of the somatostatin-signaling axis33,34 in promoting and impeding tumorigenesis, respectively, the anticancer activity of octreotide is not a surprising finding. Indeed, radiolabeled octreotide currently has a diagnostic application in oncology, allowing the detection of SSTR-positive tumors via scintigraphy (octreoscan).…”