Driver gene DNA methylation in medullary thyroid cancer

Abstract

MTC, a relatively uncommon form of cancer originating from the parafollicular C-cells of the thyroid, accounts for approximately 2-8% of thyroid cancers1. Activating mutations in the RET receptor tyrosine kinase gene are common in MTC, and KRAS or HRAS mutations also occur. Remarkably, in a recent whole exome sequencing study, no other driver mutations were identified recurrently in MTC, and the disease exhibited few mutations overall. This finding starkly emphasizes the question that drives the proposed project: What cellular changes lead to the development and progression of MTC? The hypothesis to be tested in this project is that aberrant DNA methylation is an important mechanism of tumor suppressor gene inactivation in medullary thyroid cancer (MTC). Such "driver genes" can be identified by comprehensive DNA methylation profiling and functional gene expression studies. Preliminary data from Drs. Nelkin, Ball and Baylin support this hypothesis; high throughput DNA methylation analysis identified a unique pattern of tumor suppressor gene promoter CpG island methylation in MTC. The goals of the current project are 1) confirmation and extension of the unique pattern of aberrant DNA methylation in MTC specimens, drawing on the original cohort and a validation cohort of primary surgical MTC specimens from University of Sao Paulo, and 2) functional characterization of putative aberrantly methylated tumor suppressor genes, in vitro and in MTC xenografts in vivo. Identification and characterization of such tumor suppressor genes has the potential to shed light on the biology of MTC, and to provide new therapeutic approaches and prognostic indicators in MTC. In addition to this research project, educational activities are planned during this fellowship, including scheduled discussions, as well as relevant seminars and cancer biology courses. This integrated fellowship will significantly enhance Ms. Cardoso's training for a career in cancer research. (AU)