Abstract 5077: Array CGH genomic profile of hereditary breast cancer tumors: Identification of tumor suppressor genes in deleted regions, determination of promoter hypermethylation and their protein expression in tumor biopsies

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Breast cancer, as other cancer types, is a genetic disease caused by sequential accumulation of mutations and genomic alterations involving tumor suppressor genes and oncogenes. In this matter, inactivation of tumor suppressor genes may occur by deletion, promoter hypermethylation or point mutations. We analyzed by array-CGH tumor DNA from 52 patients with hereditary breast cancer: 3 BRCA1, 4 BRCA2 and 45 from patients with no identified mutations (BRCAX). Our analysis revealed that BRCA1 mutated tumors have different genomic alterations compared to BRCA2 tumors. BRCAX tumors showed frequent deletions at: 1q21.3 (20%), 1p31.1 and 9q33.1 (18%); and frequent amplifications at 1q23.1 (20%), followed by 1q21.1 and several gains in chromosome 19 (18%). All genes involved in the deleted or amplified regions were compared with gene expression data in the ONCOMINE database finding correspondence among genomic alterations and gene expression. Based on these results, we selected 3 tumor suppressor genes for promoter methylation and protein expression analyses: RASSF1A, SLIT2 and WIF1. Methylation analysis through MS-PCR revealed that RASSF1A promoter was hypermethylated in 67% of hereditary tumors, and significantly associated to loss of expression (p=0.007, OR 9.6, CI 1.77-52.19). WIF1 promoter was hypermethylated in 68% of tumors with a significant association to loss of expression (p=0.042, OR 6.4, CI 1.155-35.45). Finally, SLIT2 was found as the most frequently hypermethylated promoter among tumors (80%) showing loss of expression in 90% of these tumors. Our results indicate that silencing of RASSF1A, SLIT2 and WIF1 through promoter hypermethylation may have an important role in hereditary breast tumor development. Fondecyt 1040779 y 1080595. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5077. doi:1538-7445.AM2012-5077