Abstract
CONTEXT: Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence. OBJECTIVE: Identify driver mutations of sporadic PC and potential actionable pathways. METHODS: Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded (FFPE) PC tumor tissue were included and their clinical data analyzed to assess extent of disease. Patients with parathyroid tumors of uncertain malignancy or atypical parathyroid neoplasms were excluded. Thirty-one patients meeting diagnostic criteria had available tissue for analysis. FFPE PC tumors were subjected to DNA extraction and next-generation whole-exome sequencing. All variant calls are single-algorithm only. Twenty-nine samples passed quality assurance after DNA extraction. MAIN OUTCOME MEASURES: Somatic or private germline mutations present in sporadic PC and identification of pathways involved in tumorigenesis. RESULTS: We identified 35 genes with considerable mutational load; only eight genes were previously identified in other PC cohorts. These genes mediate critical processes, including chromosome organization, DNA repair, and cell cycle regulations. Gene mutations involved in MAPK signaling and immune response are also heavily implicated. These findings are limited by inherent molecular artifacts in FFPE tissue analysis and the absence of matched germline DNA. Additionally, variant calls are only single algorithm and may include false-positive/negative calls. CONCLUSION: We identified 33 candidate driver genes of sporadic PC, in addition to previously known driver genes CDC73 and MEN1.