| dc.description.abstract | Genomic and transcriptomic analysis have revolutionized our understanding of many cancers. However, genomic understanding of thyroid cancer has lagged behind other tumors; currently, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. For my thesis research, I used a cohort of 251 patients with 312 thyroid lesion samples from two tertiary medical centers; these samples cover 12 unique thyroid lesion diagnoses and were deliberately enriched for aggressive thyroid cancer cases including those involving distant metastasis, recurrence, and transformation to dedifferentiated subtypes such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). We performed DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. Using our data, we characterized the mutational landscape of different thyroid cancer subtypes, identified high-risk mutations, and confirmed known patterns in thyroid cancer gene expression. In addition, we created a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, that provides improved prognostication over high-risk mutations alone. This score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment, and has the ability to identify aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Furthermore, we performed a mutational study on two cases of papillary thyroid microcarcinoma (PMC) with distant metastasis and highlight the need for improved markers for distinguishing low-risk and high-risk PMCs. In addition, we performed additional computational analyses to investigate the role of the canonical Wnt pathway, which has been implicated in the development and progressions of many cancers including thyroid cancer. Our findings indicate that changes in Wnt pathway signaling are driven by Wnt ligands rather than by Wnt pathway mutations, and also show that Wnt signaling is associated with tumor microenvironment changes as well as patient survival. Ultimately, the results of my thesis research emphasize the importance of the thyroid tumor microenvironment as a source of biomarkers which may improve prognostication, inform immunotherapy, and support the development of novel therapeutics for thyroid cancer and other stroma-rich tumors. | |
