Data from Genetic Variation in <i>IGF2</i> and <i>HTRA1</i> and Breast Cancer Risk among <i>BRCA1</i> and <i>BRCA2</i> Carriers

Abstract

<div>Abstract<p><b>Background:</b><i>BRCA1</i> and <i>BRCA2</i> mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in <i>BRCA</i> carriers.</p><p><b>Methods:</b> A cohort of 1,019 <i>BRCA1</i> and 500 <i>BRCA2</i> mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for <i>BRCA1</i> and <i>BRCA2</i> carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.</p><p><b>Results:</b> Significant associations were found between risk of breast cancer and LD blocks in <i>IGF2</i> for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers (global <i>P</i> values of 0.009 for <i>BRCA1</i> and 0.007 for <i>BRCA2</i>), <i>HTRA1</i> for <i>BRCA1</i> carriers (global <i>P</i> value of 0.005), and <i>MMP3</i> for <i>BRCA2</i> carriers (global <i>P</i> = 0.0000007 for <i>BRCA2</i>).</p><p><b>Conclusions:</b> We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in <i>BRCA1</i> carriers.</p><p><b>Impact:</b> These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in <i>BRCA1</i>and <i>BRCA2</i> mutation carriers. <i>Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR</i>.</p></div>