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.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in American women.[1]
CRC risk associated with insulin-like growth factor-I (IGF-I)/insulin resistance (IR) trait–related single-nucleotide polymorphisms (SNPs) that is mediated via IGF-I/IR traits, stratified by obesity status (BMI, waist, and w/h), level of physical activity (PA), and exogenous E use
CRC risk associated with IGF-I/IR signaling pathway–related SNPs and IGF-I/IR traits, stratified by obesity status (BMI, waist, and w/h), level of PA, and exogenous E use Because IGF-I/IR traits are not mediators of the association between SNPs in IGF-I/IR signaling-pathway genes (IRS1 and AKT1/2, in this study) and CRC, instead of estimating the mediation effect of the traits, we estimated a proportion explained by the traits as an influencing factor of the SNP–cancer relationship (Fig 2)
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in American women.[1] Incidence and death rates for CRC increase with age. The IGF-I/insulin resistance (IR) axis has been associated with CRC in multiple studies.[3,4,5] Higher levels of total/ free bioactive IGF-I and lower levels of IGF-binding protein 3 (IGFBP3) have been associated with higher CRC risk in both pre- and post-menopausal women.[3, 4, 6]. High levels of both insulin and glucose are positively associated with CRC.[4, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
