Genomic analysis of head and neck endocrine glands

Discovering biomarkers and molecular drivers of head and neck endocrine tumors was the inspiration for this thesis. Here, I describe the molecular evaluation of tumors of the thyroid and parathyroid endocrine glands for the purpose of identifying somatic driver alterations in these cancers. While molecular interplay of the germline genomic background of an individual and the somatic genome that emerges throughout the lifetime plays significant roles in increasing the susceptibility to cancer and in driving the malignant phenotype, the major known contributors to cancer remain the acquired somatic mutations. Analysis of a sporadic and recurring parathyroid carcinoma, with incidence of 1 per million population, revealed mutations in mTOR, MLL2, CDKN2C and PIK3CA and comparison of patient-matched primary and recurrent malignant tumors uncovered loss of PIK3CA activating mutation during the evolution of the tumor. Loss of the short arm of chromosome 1 along with somatic missense and truncating mutations in CDKN2C and THRAP3 provided new evidence for the potential role of these as tumor suppressors. Hürthle cell thyroid carcinoma accounts for a small proportion of all thyroid cancers; however, this malignancy often presents at an advanced stage and poses unique challenges. Genomic analysis revealed large regions of copy number variation encompassing nearly the entire genomes accompanied also by near haploidization. Moreover, I identified loss-of-function mutations of the tumor suppressor gene MEN1 in 4% of patients. Repeated alterations of the epigenetic machinery in anaplastic thyroid carcinoma, one of the most fatal of all adult solid malignancies, and novel gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11 are reported here. The transcriptomic analysis suggested known drug targets such as FGFRs, VEGFRs, KIT and RET to have low expressions in this cancer; however, through integrative data analysis, I identified the mTOR signaling pathway as a potential therapeutic target for anaplastic thyroid cancer. Molecular analysis of papillary thyroid carcinoma and benign thyroid nodules revealed very low mutation rates in these tumors with CYP1B1, PTPRE, CTSH and RUNX1 emerging as promising diagnostic markers. The key somatic mutations identified in these studies can serve as novel diagnostic markers as well as therapeutic targets.Science, Faculty ofGraduat