IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort

Abstract

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...

Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families

“…We chose to genotype non-carriers from the same families as the women participating in the study, because these women belong to the same ethnic and socioeconomic background and live in the same geographic area as the participants and are thus optimal controls. Others have reported similar frequencies for the absence of the 19-repeat allele among Caucasians ranging between 6.4 and 11.6% (Vaessen et al, 2001;DeLellis et al, 2003). The absence of the IGF1 19-repeat allele was found at a higher frequency among known BRCA1 mutation carriers (30%) compared with other women (11.5%) in the present study.…”

“…The box length is the interquartile range. the absence of the 19-repeat allele varies greatly between ethnic groups and is highest among African-American women (Jernström et al, 2001a;DeLellis et al, 2003). Missmer et al (2002) found no interaction between the absence of the 19-repeat allele and overall breast cancer risk.…”

“…Thus, on the basis of epidemiological and experimental studies, a decrease in circulating IGF-1 levels may help reduce the risk of breast cancer, especially among members of high-risk families (Furstenberger and Senn, 2002). As for postmenopausal breast cancer, neither the levels of circulating IGF-1 (Jernström and Barrett-Connor, 1999) nor the IGF1 genotype appear to affect the risk (Missmer et al, 2002;DeLellis et al, 2003). The frequency of Figure 3 (A, B) show that the IGF1 genotype modified the effect of hormonal contraceptives on the IGF-1 levels in nulliparous women.…”

“…The effect of OCs on breast cancer is generally thought to be limited to early-onset breast cancer, for example, prior to age 35 or 40 years of age (Collaborative Group on Hormonal Factors in Breast Cancer, 1996). Neither the study by Missmer et al (2002) nor the study by DeLellis et al (2003) examined the possibility that the absence of the IGF1 19-repeat allele is a latent polymorphism that only gives rise to an increased risk of early-onset breast cancer in combination with teenage OC use, and possibly pregnancy, but does not affect late-onset breast cancer. A recent case -control study of breast cancer in twins suggested that the breast tissue in women with a certain genotype might show an unusual sensitivity to pubertal hormones and an absence of linkage to hormonal milestones later in life (Hamilton and Mack, 2003).…”

Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study

“…We have not typed a CA repeat polymorphism located in the 5 0 region of IGF1, between SNPs rs35767 and rs2162679, which has been frequently included in previous studies. Several epidemiological studies on the association between this polymorphism and breast cancer risk or IGF-I levels (Jernstrom et al, 2001a;Yu et al, 2001;Figer et al, 2002;Missmer et al, 2002;DeLellis et al, 2003) have yielded highly conflicting results. This microsatellite polymorphism has a large number of alleles, which results in fractioning the study population into a large number of classes.…”