Abstract
TheMannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R)encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations betweenIGF2Rnon-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association ofIGF2Rgenetic variants and CC risk. Women homozygous for theIGF2Rc.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for theIGF2Rc.901 C>G variant. Whites homozygous for theIGF2Rc.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9–5.4)], whereas carrying theIGF2Rc.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for theIGF2Rc.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying theIGF2Rc.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.
Highlights
Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US [1,2]
Study participants were recruited as part of the North Carolina Colon Cancer Study (NCCCS) and detailed accrual methods have been described in earlier reports [26]
To gain insights into the functional significance of IGF2R genetic variants, we evaluated whether individuals who carry the IGF2R c
Summary
Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US [1,2]. Genetic variation in genes encoding insulin and insulin-like growth factors (IGF) have been evaluated in relation to CC risk the focus has been on IGF1 [4,5,6,7,8,9,10]. Few studies have evaluated IGF2, a potent mitogenic growth factor, in circulation at higher physiologic concentrations than IGF1; IGF2 has been associated with several malignancies [11]. A>G, Asn2020Ser; c.901C>G, Leu252Val and c.5002G>A Gly1619Arg] The effects of these genetic polymorphism on IGF2R function are only beginning to be elucidated in physiological studies [15,23]. G>A, that have a minor allele population frequency of more than 5%, their association with higher IGF2 circulating levels, and colon cancer risk in African Americans and Whites We evaluate two of the three non-synonymous IGFR2 variants, c.901 C>G and c.5002 G>A, that have a minor allele population frequency of more than 5%, their association with higher IGF2 circulating levels, and colon cancer risk in African Americans and Whites
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