Triple Negative Breast Tumor Methylation Profile assessed by MS-MLPA

BRANHAM M.T.; MARZESE D.M.; LAURITO S.R.; GAGO F.E.; OROZCO J.I.; TELLO O.M.; VARGAS ROIG L.M.; ROQUÉ, M.

Mallorca

Congreso; International Society of Cellular Oncology (ISCO) 2012 Congress; 2012

International Society of Cellular Oncology (ISCO)

Breast cancer is a group of clinically, histopathologically and molecularly heterogeneous diseases, with different outcomes and responses to treatment. ER-/PR- and HER2- is an immunohistochemical description of Triple Negative breast (TNB) tumors. The hypermethylation of CpG islands (CpGI) is a common epigenetic alteration for suppressing gene expression in breast cancer and has been shown to be a key factor in breast carcinogenesis. In this study we analyzed the epigenetic profile of TNB tumors. Methods: For the methylation analysis, we used the methyl specific-multiplex ligation probe amplification assay (MS-MLPA). Fifty invasive ductal carcinomas were included in the study. We analyzed 110 CpGI within 69 genes. Results: We found that the methylation index between TNB and non-TNB tumors was similar, but the methylated genes between the groups were different. The methylation profile of TNB tumors is defined by the methylation of 5 genes: i.e. CDKN2B, CD44, MGMT, RB and p73, plus the non-methylation of 11 genes, i.e. GSTP1, PMS2, MSH2, MLH1, MSH3, MSH6, DLC1, CACNA1A, CACNA1G, TWIST1 and ID4. Conclusions: To our knowledge this is the first report demonstrating a 16-genes methylation signature of TNB tumors. It is interesting to note that, although it has been reported that TNB tumors present genomic instability, the methylation of mismatch repair (MMR) genes is significantly not affected. The known down-regulation of the BRCA1 pathway could be explained by the significantly non methylation of its repressor ID4. MMR proteins mediate the response to certain DNA damaging agents such as cisplatin, which can modify the structure of nucleic bases. Based on the epigenetic evidence of our results, TNB tumors could be responsive to these treatments. Another attractive result is that TNB tumors present significantly differential methylation of MGMT gene. The presence of methylation on this gene is an indicator of susceptibility to the drug temozolomide. Our findings add novel information to better understand tumor etiology, and encourage future studies on therapeutic targets for Triple Negative breast tumors, which now lack of a specific treatment.