Abstract 3029: A KRAS microRNA binding site polymorphism as a novel biomarker of risk in triple negative breast cancer
Authors: Paranjape Trupti S. , Heneghan Helen , Pelletier Cory , Hoffman Aaron , Kerin Michael J. , Harris Lyndsay , Zhu Yong , Miller Nicola , Zelterman Daniel , Tuck David , Slack Frank , Weidhaas Joanne 
Published: February 2011

Abstract
The purpose of our study is to determine the role of a previously identified novel germline polymorphism in the let-7 miRNA binding site in the 3’UTR of the KRAS oncogene, referred to as the KRAS-variant, as a biomarker of breast cancer risk. We have shown that the KRAS-variant is a biomarker of increased risk of ovarian cancer for patients from families with Hereditary Breast and Ovarian Cancer. Thus, in this study, we tested the association of this biomarker with breast cancer using: i) A BC case-control recruited at Yale, ii) A cohort of Irish Caucasian women diagnosed with known BC subtypes and iii) A cohort of triple negative (TN) BC patients at Yale, all with known demographics and clinical variables. We assayed for the prevalence of the KRAS-variant by SNP genotyping to determine its association with BC. We compared the prevalence of the KRAS-variant in different BC subtypes and evaluated the association with age and ethnicity. MiRNA profiling was performed on the subjects in the TN BC cohort using Taqman low density miRNA microarrays. We analyzed the miRNA expression patterns within the TN BC cohort and also compared the miRNA expression patterns in the KRAS-variant positive and negative patients also evaluating the association with the age and ethnicity using linear modeling methods. We are currently performing gene expression analysis on the same TN BC patients that we have miRNA expression analysis and KRAS-variant testing completed on. We will compare gene expression patterns with the unique miRNA signatures in the KRAS-variant positive versus negative cases. We plan to use network programs to evaluate similarities in gene expression by miRNA, and also evaluate known targets of misexpressed miRNAs and determine their levels. In the BC case-control the KRAS-variant was found to be significantly associated with the ER/PR- BC patients below 51 yrs (33% vs. 10.5% for controls and ER/PR+). In the Irish Caucasian BC cohort the KRAS-variant was most prevalent in the TN BC patients (21.7% vs. 12-14% for Luminal A and Bs) below 51yrs. Consistently in the TN BC cohort the KRAS-variant was most prevalent in non-African American (AA) women below 51 yrs (33% vs. 21.5% in women of all races below 51 yrs). Through miRNA profiling we found that miRNA signatures vary across the TN BC patients, suggesting the existence of different groups within the TN cohort itself. The young non-AA TN BC patients appeared to have lower miRNA expression overall and clustered together. We also found that the KRAS-variant is associated with a unique miRNA expression pattern in TN BC patients with the variant compared to those without. A miRNA binding site polymorphism in the 3’UTR of the KRAS gene, the KRAS-variant, is a new biomarker of risk for developing triple negative BC in young non-AA women. In addition, KRAS-variant patient tumors have unique miRNA signatures and preliminary data supports they also have common gene expression differences.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3029.