Abstract 4356: Methylation and expression of androgen receptor in Papillary Thyroid Cancer

Abstract

Abstract Papillary Thyroid Cancer (PTC) accounts for the vast majority of thyroid cancers and comprises more than 90% of neoplasms in the endocrine system. In the last 30 years, the incidence and prevalence of PTC has dramatically risen in developed countries, with a three-fold higher incidence in women than in men. With an overall five-year survival rate of 98.1%, early stage PTC has a favorable prognosis. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These striking observations led us to explore the role of androgen and androgen receptor (AR) in this disease. We found an approximately 70% decrease in median AR RNA expression (p<0.0001) in 24 PTC patient tissue samples (from New York Eye and Ear Infirmary), compared to matched, normal thyroid tissue. A similar trend was also observed in about 500 PTC samples in the TCGA database, compared with 60 normal thyroid samples. Methylation was explored as a cause for the down-regulation of the AR mRNA in disease pathogenesis, using in-silico methods such as Wanderer, a Maplab tool for TCGA RNA data visualization, and MethylPlotter. A methylation pattern of the AR gene, spanning 7 exons, was generated with 30 methylation sites and, AR in PTC was found to be predominantly methylated at ten sites, compared to matched normal thyroid tissue samples, in the TCGA. Patients with ten or more hypermethylated sites on the AR gene in tumor tissue exhibited a significant decrease in the AR RNA expression in the tumor, versus matched normal thyroid tissue. Methylation of AR (10 or more sites) was accompanied by a nine-fold reduction in AR expression in male PTC, and a five-fold decrease in female PTC. This reduction was not observed in hyper- or equally-methylated normal thyroid tissue. We selected eleven methylation sites in the CpG islands that we predict are essential for AR silencing, with four sites in the AR promoter region. Additionally, we found AR gene-specific and global transcription activators to be downregulated, and repressors up-regulated in the PTC samples. The data adds importance to our previous studies showing induction of senescence in AR-transfected PTC cells in culture, when AR is stimulated with 5α-dihydrotestosterone. In conclusion, our study demonstrates a fine regulation and differential expression of AR associated with methylation, and highlights the significance of epigenetic modifications in thyroid cancer progression. Citation Format: Anvita Gupta, Timmy O'Connell, Melanie Jones, Karnika Singh, Monica Schwarcz, JK Rasamny, Dorota Halicka, Jiangwei Li, Codrin Iacob, Nina Suslina, Stimson Schantz, Edward Shin, Zbigniew Darzynkiewicz, Raj Tiwari, Jan Geliebter. Methylation and expression of androgen receptor in Papillary Thyroid Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2017-4356