Insulin-like Growth Factor-1 Receptor Variant Associated With Decreased Breast Cancer Risk in Women With Pregnancy-Induced Hypertension

Mark Powell, LeeAnn Prebil, Sam Rose, Farid Jamshidian, Chris Benz* and Rochelle EremanMarin Women’s Study, Marin County Health & Human Services; *Buck Institute for Research on Aging

Materials and Methods

Background

Objective

Results

Acknowledgements

•Pregnancy-induced hypertension (Gestational hypertension and Preeclampsia) affects 6-8% of pregnancies and is characterized by the new onset of hypertension after 20 weeks of gestation. [1]

•Many studies have demonstrated a lower breast cancer risk in women who have experienced pregnancy induced hypertension (PIH). [2,3]

•Analyses in the Marin Women’s Study have demonstrated that these women may also have lower breast density later in life. [4]

•Current hypotheses for these observations center on the release of maternal metabolic factors which result from the incomplete placentation seen in these women, although the exact mechanism for the observed protection is as yet unexplained. [5]

The second phase of the analysis examined the interaction of the VEGF and IGF1R SNPs with PIH on breast cancer case status. This analysis included all 374 women in the MWS with a history of PIH, case status, and DNA genotype results. There was no significant interaction between the VEGF SNP and PIH on breast cancer, however there was a statistically significant interaction between the IGF1R TT SNP and PIH on breast cancer as shown below:

The sample size of parous women for the first phase analysis was 1240. After adjusting for potential confounders including age, race, age of first birth, and current BMI, 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).

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To look for gene/environment interactions that might (1) better identify which women with PIH have breast cancer protection and (2) shed light on the mechanism of this protection.

Materials and Methods

The study was carried out in the Marin Women’s Study (MWS) which was initiated in 2006 to examine breast cancer in Marin County, an area with high breast cancer incidence rates. 13,344 women were enrolled at mammography sites in Marin that are part of the San Francisco Mammography Registry, one of seven registries that make up the National Cancer Institute Breast Cancer Consortium. An initial study of pregnancy characteristics and breast density in the MWS demonstrated a lower breast density in women with a history of PIH. The current two-phased study was designed to assess whether this apparent protective effect is modified by individual genetic differences.

Participants self-reported reproductive histories and other personal history data on the MWS questionnaire at the time of enrollment. Compositional breast density using single X-ray absorptiometry (SXA) was measured on digital mammography examinations by the San Francisco Mammography Registry. DNA was extracted from donated saliva specimens. Case status data were obtained from the California Cancer Registry.

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

The selected SNPs are summarized in the following table:

Gene Gene Name SNP ID Allele Frequency Gene Functions

NOS3 Nitric oxide synthase 3 rs2070744 0.29T, 0.71C Anti-tumor activities/ Vascular tone

ESR2 Estrogen receptor 2 (ER β) rs928554 0.64A, 0.36G Hormone receptors/ Steroid hormone metabolism

VEGF Vascular endothelial growth factor A rs3025039 0.87C, 0.13T Angiogenesis

EDN1 Endothelin 1 rs5370 0.82G, 0.18T Vasoconstriction

IL-10 Interleukin 10 rs1800896 0.53G, 0.47A Immune Modulators/Cytokines

KLKB1 Kallikrein B, Human Coagulation Factor XI

rs925453 0.67C, 0.33T Inflammatory response

IGF1R Insulin-like growth factor 1 receptor rs2016347 0.55T, 0.45C Cell Growth and Development

Objective Results

Materials and Methods

This graph illustrates that women having PIH and the GG genotype of IGF1R had little change in their breast density, while those with both the GT and TT genotypes had significant decreases in density.

Interaction of PIH History and IGF1R

IGF1R genotype Number with genotype Number breast cancer cases %cases

GG 91 8 8.79%

GT 195 14 7.18%

TT 88 0 0.00%

Breast cancer cases in women with PIH and IGF1R genotype

Fisher’s exact = 0.008

Of note, there was no statistical association between the IGF1R TT SNP and case status, with 27.1% of breast cancer cases having the IGF1R TT genotype (108/398) compared to 27.0% of controls (382/1415).

•Women with a history of PIH had a significantly lower risk of breast cancer only if they had a specific genotype of the IGF1R SNP, and this genotype was also associated with lower breast density in these women.

•Since this same 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. [6]

Conclusions/Discussion

The Marin Women’s Study is funded by the Centers for Disease Control and Prevention and the Avon Foundation for Women, and conducted in collaboration with clinical and community partners: Buck Institute for Research on Aging, University of California, San Francisco School of Medicine, Kaiser Permanente San Rafael, Marin Cancer Institute at Marin General Hospital, Cancer Prevention Institute of California, and Zero Breast Cancer.

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GG GT TT

No PIH

Yes PIH

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References1. Leeman L, Fontaine P. Hypertensive disorders of pregnancy. Am Fam Physician. 2008 Jul 1;78(1):93-100.2. Opdahl S, Romundstad PR, Alsaker MD, Vatten LJ. Hypertensive diseases in pregnancy and breast cancer risk. Br J Cancer 2012 Jun 26;107(1):176-82.3. Vatten LJ, Romunstad PR, Trichopoulos D, Skjaerven R. Pre-eclampsia in pregnancy and subsequent risk for breast cancer. Br J Cancer 2002;87:971-973.4. Prebil LA, Ereman R, Powell M, Kerlikowske K, Shepherd J, Hurlbert M, Puckett RL, Benz CC First pregnancy events determine future breast density independent of systemic sex steroid levels . 33RD Annual San Antonio Breast Cancer Symposium: December, 2010.5. Gingery A, Bahe EL, Gilbert JS. Placental ischemia and breast cancer risk after preeclampsia: tying the knot. Expert Rev Anticancer Ther. 2009. May;9(5):671-81.6. Winder T, Giamas G, Wilson PM, Zhang W, Yang D, Bohanes P, Ning Y, Gerger A, Stebbing J, Lenz HJ. Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen. Pharmacogenomics J. 2013Mar 5. doi:10.1038/tpj.2013.8