title: Insulin-like growth factor-1 genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating insulin-like growth factor-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families.
abstract: BACKGROUND
  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 that may also modify the risk in BRCA1/2 mutation carriers. The absence of the IGF1 19-CA repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use in nulliparous women of four different ethnic groups. High IGF-1 levels are linked to an increased risk of early-onset breast cancer and to larger breast volumes in the general population. It has also been hypothesized that women whose breast size increases while exposed to OCs may be at increased risk of future breast cancer.
  
  
  OBJECTIVE
  We explored the effect of the IGF1 genotype, specifically the absence of the common 19-CA repeat allele in the promoter region of the IGF1 gene, in combination with oral contraceptive (OC) use or parity on breast volume and IGF-1 levels.
  
  
  METHODS
  Two hundred fifty-eight healthy women, </=40 years old, from hereditary breast cancer families participated in this prospective study. Twenty-three women were known BRCA1 mutation carriers, 7 women were known BRCA2 mutation carriers, 54 women were noncarriers from BRCA1/2 families, 111 women belonged to breast cancer families where no BRCA1 or BRCA2 mutations were detected, and 63 women were untested from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured height, weight, breast volumes, and plasma IGF-1 levels once during menstrual cycle days 5-10 and once again during menstrual cycle days 18-23. The IGF1 genotype was successfully analyzed with polymerase chain reaction and fragment analyses in 254 women.
  
  
  RESULTS
  Thirteen percent had no IGF1 19-CA repeat allele. The absence of the 19-CA repeat allele was more common among women with known BRCA1 mutations compared to other women (26% versus 12%; P= 0.05). See updated and revised Table 1 from original publication. IGF-1 levels were similar among parous and nulliparous women not using OCs, which is in contrast to results from women in the general population, where parous women have lower IGF-1 levels than nulliparous women. Furthermore, OC use did not affect IGF-1 levels in parous women in our study. BRCA mutation status did not affect age-adjusted IGF-1 levels in either cycle phase among nonusers. Most of the nulliparous OC users had lower IGF-1 levels than nonusers. However, there was an interaction between IGF1 genotype and OC use on IGF-1 levels in nulliparous women (P= 0.026). Compared with nonusers, IGF-1 levels were highly suppressed in OC users with a 19-CA repeat allele (P < 0.001), but not among women lacking the 19-CA repeat allele (P= 0.81). We also observed an interaction between parity and IGF1 genotype on breast volume (P= 0.01). Absence of the 19-CA repeat allele was associated with larger breast volumes in parous versus nulliparous women and OC users, while parous women and OC users with the 19-CA repeat allele had smaller breast volumes than nulliparous women and nonusers adjusted for body weight. During follow-up, six incident breast cancers cases occurred, four in known BRCA1 mutation carriers and two in untested women. Incident breast cancers were associated with absence of the 19-CA repeat allele (log-rank; P= 0.002).
  
  
  CONCLUSIONS
  Our results suggest that absence of the IGF1 19-CA repeat allele modifies IGF-1 levels, breast volume, and possibly early-onset breast cancer risk after hormone exposure in young, high-risk women. These results warrant confirmation in a larger prospective cohort of high-risk women. If confirmed, the IGF1 genotype could be incorporated as an additional marker to improve risk estimates for early-onset breast cancer during genetic counseling of women from high-risk breast cancer families.
authors.affiliation: Department of Oncology, Lund University, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Jernström
authors.forename: T
authors.initials: T
authors.lastname: Sandberg
authors.forename: E
authors.initials: E
authors.lastname: Bågeman
authors.forename: A
authors.initials: A
authors.lastname: Borg
authors.forename: H
authors.initials: H
authors.lastname: Olsson
mesh_terms: D017668:Age of Onset; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D003278:Contraceptives, Oral, Hormonal / Q000097:blood*; D018900:Dinucleotide Repeats / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000097:blood / Q000453:epidemiology / Q000473:pathology*; D011446:Prospective Studies; D013548:Sweden / Q000453:epidemiology
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D003278:Contraceptives, Oral, Hormonal; D007334:Insulin-Like Growth Factor I