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Comparative Study
, 92 (5), 857-66

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

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Comparative Study

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

H Jernström et al. Br J Cancer.

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 < or =40 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=0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P=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=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.

Figures

Figure 1
Figure 1
The figure shows the proposed mechanisms by which we hypothesise that absence of the IGF1 19-repeat allele in combination with hormone exposure would increase the breast volume and the risk of early-onset breast cancer. References to the steps that have been previously explored are indicted. The risk of early-onset breast cancer after hormone exposure may be partially modified through the IGF-1 pathway.
Figure 2
Figure 2
(A, B) show that there were no significant differences in median IGF-1 levels between parous and nulliparous women not currently using any hormonal contraception in the samples obtained during cycle days 5–10 (P=0.57) or in the samples obtained during cycle days 18–23, that is, 5–10 days prior to the predicted onset of the next menstrual period (P=0.49). The horizontal line in the box indicates the median value, the box boundaries the 25th and 75th percentiles, and the capped bars the 10th and the 90th percentiles. The number of women in each group is indicated. Circles indicate outliers with values between 1.5 and 3 box lengths from the upper or lower edge of the box. Asterisks indicate extreme outliers with values more than 3 box lengths from the upper or lower edge of the box. The box length is the interquartile range.
Figure 3
Figure 3
(A, B) show that the IGF1 genotype modified the effect of hormonal contraceptives on the IGF-1 levels in nulliparous women. The interaction between IGF-1 genotype and hormonal contraception was nonsignificant during cycle days 5–10 (P=0.13) and significant during cycle days 18–23, that is, 5–10 days prior to the predicted onset of the next menstrual period (P=0.026). The horizontal line in the box indicates the median value, the box boundaries the 25th and 75th percentiles, and the capped bars the 10th and the 90th percentiles. The number of women in each group is indicated. Circles indicate outliers with values between 1.5 and 3 box lengths from the upper or lower edge of the box. Asterisks indicate extreme outliers with values more than 3 box lengths from the upper or lower edge of the box. The box length is the interquartile range.
Figure 4
Figure 4
The figure shows the cumulative breast-cancer-free survival after study entry in women with and without the IGF1 19-repeat allele. The difference between the two groups was significant (log-rank P=0.002). Follow-up was censored at the time of prophylactic mastectomy without detection of breast cancer or on March 31, 2003. Please note the broken Y-axis. The number of women at each time point is indicated.

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