Abstract 3829: DNA methylation profile in papillary thyroid cancer according to BRAF (V600E) mutation

Abstract

Abstract Background: Thyroid cancer is an important health burden and the endocrine neoplasia with highest incidence in worldwide. Papillary thyroid cancer (PTC), the most common thyroid malignancy, is frequently associated with BRAF V600E mutation. This mutation occurs in around 45% of PTC cases and it has been associated with aberrant gene methylation. This finding suggests an association between genetic and epigenetic alterations in tumor development. The goal of this study was to evaluate the methylation profile in PTC samples according to BRAF mutation. Patients and Method: Forty-two PTC were included in this study (28 positive for BRAF V600E mutation). Normal and tumoral samples were obtained from patients submitted to total thyroidectomy and radioiodine therapy. The pyrosequencing method was used to detect and quantify the BRAF V600E mutation in tumor samples. The methylation analysis was performed by microarray platform Methylation 450 Human Infinium®BeadChip (Illumina), according to the manufacturer's recommendations. The data were normalized and analyzed using SVA, wateRmelon and LIMMA package. It was considered only probes with Delta-Beta (β) = 0.1 and p value ≤ 0.001. Integrative analyses were performed using expression data generated from previous analysis. The findings were compared with 56 samples from The Cancer Genome Atlas (TCGA). Genes enrichment to biological pathways were performed using Ingenuity Pathway Analysis software. Results: It was identified 404 differentially methylated probes (291 hypomethylated and 113 hypermethylated) of which 195 were validated by TCGA. After the integrative analysis with expression data, nine TOP genes (INF2, TACSTD2, RAB15, TM7SF4, GJB3, CDSN, BHLHE41, GTF2IRD1, CXXC5) were selected with hypomethylation and overexpression. Three of them, BHLHE41, CDSN and INF2, were enriched to cancer and endocrine system disorders pathways (P = 4,47×10−2), highlighting the relevance of these genes in PTC Conclusion: This study point out putative drivers in PTC according to BRAF mutation revealing epigenetic mechanisms that contributes with cell proliferation and aggressiveness in thyroid carcinoma. Citation Format: Caroline Moraes Beltrami, Mariana Bisarro dos Reis, Mateus Camargo Barros-Filho, Fabio Albuquerque Marchi, Hellen Kuasne, Srikant Ambatipudi, Zdenko Herceg, Luiz Paulo Kowalski, Silvia Regina Rogatto. DNA methylation profile in papillary thyroid cancer according to BRAF (V600E) mutation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3829. doi:10.1158/1538-7445.AM2015-3829