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Molecular profiling of papillary thyroid carcinoma has largely been confined to exome sequencing of non-aggressive cancer.1,2 Canonical mutations in BRAF and RAS are significantly represented in thyroid tumors, but these mutations have not resulted in diagnostics and therapeutics for advanced disease. To broadly examine the molecular landscape of advanced disease, we conducted a multi-omic analysis of 34 cases of advanced papillary thyroid carcinoma, including patient-matched lymph node metastases, primary tumor, adjacent-normal thyroid and germline. Our genome-wide multi-omic analysis links the regions of activated chromatin with expressed transcripts and proteins, identifying regulatory elements at primary tumor and nodal metastases stages of thyroid cancer progression. Distal regulatory elements putatively upregulate expression of MAPK-pathway genes in both tumors and metastases (36 genes (p =0.0057) in tumors and 76 genes (p =0.0011) in metastases). Furthermore, tumors and metastases harbor accessible chromatin regions that appear to be bound by MAPK transcription factors, FOS and JUN (p-value &amp;lt;10-150 for tumors and metastases). This study identifies regulatory elements that mediate MAPK activity in tumors and metastases of advanced papillary thyroid carcinoma and may ultimately lead to diagnostics and therapeutics that utilize advanced-thyroid-cancer-specific epigenetic targets. References • Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014 • Masoodi T, et al. Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer. Thyroid. 2020

SAT-LB25 A Multi-Omics Analysis of Advanced Papillary Thyroid Cancer