Abstract P3-07-03: Insulin-like growth factor-1 receptor variant associated with decreased breast cancer risk in women with pregnancy-induced hypertension

Introduction: Studies have reported a lower breast cancer risk in women who have experienced pregnancy induced hypertension (PIH). Current hypotheses for these observations center on placental dysfunction and a subsequent alteration of levels of circulating hormones, growth factors, and angiogenic and immune modulators.

The Marin Women's Study (MWS) was initiated in 2006 to examine breast cancer in Marin County, an area with historically high breast cancer rates. Enrollment of 13,365 women occurred at mammography sites that participate in the San Francisco Mammography Registry (SFMR), one of seven registries included in the NCI Breast Cancer Consortium. In a prior analysis of MWS data, we demonstrated that PIH is associated with reduced breast density later in life, and the current two-phased study was designed to assess whether this apparent protective effect is modified by individual genetic differences.

Methods: Participants self-reported reproductive history and risk factors on the MWS questionnaire at the time of enrollment. Compositional breast density using single X-ray absorptiometry (SXA) was measured on digital mammography. These readings and breast cancer case status data obtained from the California Cancer Registry was acquired by cooperative agreements with the SFMR. DNA for SNP analyses was extracted from donated saliva specimens.

The first phase analysis focused on breast density and assessed the interaction of 7 SNPs of specific selected genes with a history of PIH. A second phase analysis focused on breast cancer case status for any SNP which appeared to demonstrate interaction in the initial analysis.

Results: After adjusting for potential confounders, only the IGF1R SNP (rs2016347) demonstrated a statistically significant interaction with PIH on mammographic density (GT, p = 0.01, and TT, p = 0.07 compared to baseline GG), although the VEGF SNP (rs3025039) approached statistical significance (CT, p = 0.06 compared to baseline CC) in our sample size of 1240 women.

The second phase of the analysis examined the association of the VEGF and IGF1R SNPs with breast cancer case status in all women in the MWS with a history of PIH, saliva specimen, and case status data (n = 374). There was a statistically significant decrease in breast cancer risk in women with PIH and the IGF1R SNP as shown below:

There was no statistical association between this SNP and PIH incidence or case status in women without PIH, where 27.1% of breast cancer cases had the IGF1R TT genotype (108/398).

Conclusions: Women with a history of PIH had a lower risk of breast cancer if they had the TT genotype of the IGF1R SNP (rs2016347), and this genotype was also associated with lower breast density. Since this IGF1R variant has previously been associated with mammographic density and found to be an independent prognostic marker for breast cancer recurrence, its expression may play a breast cancer protective role by reducing mammographic density in women with PIH.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-03.