ABSTRACT Thyroid cancer is less frequent but deadlier for individuals who self-identify as African American/ Black or Latino/Hispanic in comparison to individuals who self-identify as White/European American. Thyroid cancer mortality in individuals who self-identify as Hispanic is higher than in individuals who self-identify as White/European American. At the same time, thyroid cancer patients who self-identify as African American/ Black are associated with worse overall survival than patients who self-identify as White/European Americans. There are many reasons for these disparities in survival and mortality including lack of insurance, poor access to care, and low quality of health care; however, there is emerging evidence that biology may also play a role. In our funded R01, we aim to validate the DNA methylation panel with 373 biomarkers to improve pre-operative early detection of thyroid cancer. This does not include genetic ancestry. To date, we have obtained 779 of 4550 thyroid biopsies from six highly diverse centers; 100 biopsies are from individuals who self-identify as non-Hispanic White, and 49 from individuals who self-identify as African American/Black. Here we aim to perform a comprehensive gene expression and DNA methylation analysis of thyroid nodules from individuals who self-identify as non-Hispanic White or African American/Black and compare with individuals who self- identify as non-Hispanic White and test for race-specific differences. The analysis will be done based on genetic ancestry. Our goal is to identify race-specific differences in gene expression and DNA methylation to better understand disparities in thyroid cancer mortality and survival. We plan to accomplish our overall objective for this project by pursuing the following specific aims: Aim 1: Analysis of race-specific transcriptional activity in benign and malignant nodules from Hispanic Whites, African Americans, and non-Hispanic Whites. Aim 2: Analysis of race-specific DNA methylation in benign and malignant nodules from Hispanic Whites, African Americans, and non-Hispanic Whites and alignment of these data with race-specific gene expression. This proposal addresses two important cancer disparity questions: the role of gene activity, and the role of epigenetic changes in thyroid cancer disparities, respectively. By elucidating biological mechanisms driving thyroid cancer disparities, our study has the potential to reduce morbidity and mortality associated with thyroid cancer disparities and promote health equity.