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

Abstract

BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low-penetrance genes, which may also modify the risk in BRCA mutation carriers. The absence of the IGF1 19-repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use. High IGF-1 levels are linked to early-onset breast cancer and larger breast volumes in the general population. The goal of this study was to elucidate the relationships between IGF1 genotype, early-onset breast cancer, breast volume, circulating IGF-1 levels and OC use in a prospective cohort of 258 healthy women p40 years old from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured the height, weight, breast volumes and plasma IGF-1 levels. IGF-1 levels were similar among parous and nulliparous women not using OCs. In all, 13% had no IGF1 19-repeat allele. There was an interaction between IGF1 genotype and OC use on IGF-1 levels (P ¼ 0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P ¼ 0.01). Absence of the 19-repeat allele was associated with high IGF-1 levels in nulliparous OC users and with larger breast volumes in parous women and OC users. Incident breast cancers were also more common in women without the 19-repeat allele (log rank P ¼ 0.002). Our results suggest that lack of the IGF1 19-repeat allele modifies IGF-1 levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high-risk women.

IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families

“…The first inclusion arm has been described in detail elsewhere [17]. In brief, 267 young healthy women with no previous cancer history or prophylactic mastectomy or bilateral oophorectomy were enrolled in the study between 1996 and 2006.…”

Absence of the common IGF1 19 CA-repeat allele is more common among BRCA1 mutation carriers than among non-carriers from BRCA1 families

“…We also had access to the IGF1 genotypes of 72 healthy 18 -40 year-old women from BRCA1 mutation families who constituted part of our previous study population (Jernström et al, 2005). A woman who was included in the previous study was not included in the new study population and no woman belonged to both of these study populations.…”

“…We also had access to IGF1 genotypes for 254 women from our previous study of young healthy high-risk women (Jernström et al, 2005). All the IGF1 genotyping in this study was done on the ABI3100 Genetic analyzer as specified above.…”

“…The risk is not identical for all mutation carriers, but is also influenced by allelic heterogeneity, low-penetrance modifying genes and environmental and hormonal factors (Narod & Foulkes, 2004). Absence of the common 19-CA repeat allele of the IGF1 (IGF1-19/-19) gene is associated with early-onset breast cancer after oral contraceptive (OC) use (Cleveland et al, 2006;Jernström et al, 2005) and in multiparous women (Bågeman et al, 2007) and may therefore be one such modifying gene.…”

“…We have previously reported that the IGF1-19/-19 genotype was more common among known BRCA1 mutation carriers than among other healthy women from highrisk breast cancer families of various types (i.e. BRCA1, BRCA2, BRCAX and untested families) (Jernström et al, 2005). The number of women with a known BRCA1 mutation was fairly small and the comparison was made with all the other women from high-risk families.…”