The insulin-like growth factor 1 gene (IGF1) is a strong candidate gene for a breast cancer susceptibility model. We investigated a dinucleotide repeat 969 bp upstream from the transcription start site of the IGF1 gene for possible associations with plasma IGF1 levels and breast cancer risk in a multiethnic group of postmenopausal women. Furthermore, we investigated the relation between race/ethnicity, mean plasma IGF1 levels and breast cancer rates in the Hawaii/Los Angeles Multiethnic Cohort. The mean ageadjusted IGF1 level among Latino-American women, 116 ng ml À1 , was statistically significantly lower than the mean age-adjusted IGF1 levels for each of the three other racial/ethnic groups, African-American, Japanese-American and Non-Latino White women (146, 144 and 145 ng ml À1 , respectively) (Po0.0001). Latino-American women have the lowest breast cancer rates of any racial/ethnic group in the cohort. These results support the investigation of an expansion of the hypothesis for an important role of IGF1 in breast cancer tumorigenesis to different racial/ethnic groups and to postmenopausal women. It is unlikely that any involvement of IGF1 in breast cancer aetiology is mediated by the IGF1 dinucleotide repeat polymorphism, which was not significantly associated with circulating IGF1 levels nor breast cancer risk in this study. Research into relevant determinants of IGF1 levels in the blood must continue. British Journal of Cancer (2003) The insulin-like growth factor 1 (IGF1) protein has been implicated in breast cancer because of its mitogenic and antiapoptotic effect on mammary epithelial cells (Furlanetto and DiCarlo, 1984;Westley and May, 1994;Kleinberg, 1998). Epidemiological work epitomised by a paper from Hankinson et al (1998) has shown an increased risk for breast cancer in premenopausal women with high prediagnostic plasma IGF1. Byrne et al (2000) subsequently showed that mammographic density, one of the strongest breast cancer risk factors, was positively correlated with plasma IGF1 in premenopausal but not postmenopausal control women. Although these initial findings were limited to premenopausal women, postmenopausal IGF1 levels may also be an important determinant of breast cancer risk if considered as a component of lifetime or intratissue exposure. Assessment of lifetime or intratissue exposure may be improved by the availability of genetic determinants. An early report suggested that the homozygous status for a (CA) 19 microsatellite variant 969 bp upstream from the transcription start site in the IGF1 gene (IGF1) was predictive of low serum IGF1 in Caucasian men and postmenopausal women. We hypothesised that the (CA) 19 homozygous genotype (19/19) might indicate women with a decreased lifetime exposure to IGF1 and consequently, a decreased susceptibility to breast cancer. We examined the role of IGF1 in postmenopausal breast cancer among women from four major racial/ethnic groups (African American, Japanese American, Latino American, White) in the Hawaii and Los Angeles Multiethnic Cohort...

Elevated levels of plasma insulin-like growth factor I (IGF-I) are a potential risk factor for several cancers, including colorectal cancer. Physiologic levels of plasma IGF-I vary greatly; this variation may be in part genetically determined. We identified two single nucleotide polymorphisms (SNP) in perfect linkage disequilibrium with each other and in partial linkage disequilibrium with a previously studied cytosine-adenine microsatellite [-969(CA)n]. We investigated one of the SNPs, -533T/C,and the 969(CA)n in relation to the risk of colorectal cancer in a case-control study nested within a cohort of Singapore Chinese (cases/controls = 290:873). The (CA)21 allele, rather than the previously implicated (CA)19 allele, was associated with a reduced risk of colorectal cancer (odds ratio for 21/21 versus all other genotypes, 0.48; 95% confidence interval, 0.28-0.84). For the -533C/T SNP, persons carrying one or more copies of the C allele had a decreased in risk of colorectal cancer compared with noncarriers (odds ratio for CC/CT versus TT, 0.58; 95% confidence interval, 0.41-0.82). This association was specific for colon, as opposed to rectal cancer and was modified by age. We also examined a functional insulin-like growth factor binding protein (IGFBP3) promoter SNP, -202 A/C, previously reported to predict serum IGFBP3 levels. Although we were able to confirm this genotype-phenotype association, the -202A/C IGFBP3 SNP was not significantly associated with colorectal cancer risk. In conclusion, we report a novel SNP in the IGF-I regulatory region that is associated with colorectal cancer risk.

High circulating concentration of insulin-like growth factor-I (IGF-I) and low circulating concentration of IGF binding protein-3 (IGFBP-3) have been associated with increased risk for breast, prostate, and colorectal cancers. Building on previous work in the Multiethnic Cohort (MEC) showing significant differences in IGF-I levels across racial/ethnic groups, we investigated which lifestyle and dietary factors are associated with levels of IGF-I and IGFBP-3 in a random sample of 1,000 MEC participants, which included Native Hawaiian, African American, Japanese, Latino, and White men and women. Crude analyses confirmed the existence of differences in protein levels with race/ethnicity, sex, age, and body size. Reproductive, physical activity, smoking, and diet variables had less consistent effects. In multivariate analyses, IGF-I levels were lower and IGFBP-3 were higher in females versus males. IGF-I and IGFBP-3 declined with increasing age in both genders. Women in the highest quartile of body mass index showed depressed IGF-I and IGFBP-3 levels; in men, height was significantly positively associated with both proteins. In women, alcohol was directly associated with IGFBP-3. Both proteins were lowest among female Latinos. IGF-I was highest among female African Americans. In men, IGFBP-3 was lowest among African Americans. Overall, although these factors were statistically significant determinants of IGF-related protein levels, they did not explain much of the variation in these levels. A positive correlation was found between IGF-I levels (ng/mL) and colon cancer incidence rates (per 100,000) within the MEC by race/ethnicity for both sexes but not for either breast or prostate cancer.