CDC73 encodes parafibromin, a tumor suppressor and core component of the PAF1 complex (PAF1C) that regulates transcription by RNA polymerase II. 1 The PAF1C facilitates transcriptional elongation and is involved in histone modifications, including H2B ubiquitination and H3K4 methylation, as well as mRNA 3' end processing. 1 CDC73 plays critical roles in transcriptional regulation of Hox and Wnt target genes and is essential for hematopoiesis. 1 In T-ALL, CDC73 intersects with Notch and ETS1 at chr1 to activate oncogenes while also promoting DNA repair and mitochondrial function gene expression programs. 2 Clinically, CDC73 mutations are the most significant molecular driver of parathyroid carcinoma, identified in up to 70% of cases, with approximately one-third being germline mutations. 3 4 CDC73 germline mutations cause hyperparathyroidism-jaw tumor syndrome (HJT), characterized by primary hyperparathyroidism in ~85% of carriers, with parathyroid carcinoma occurring in up to 15% of HJT cases compared to <1% in sporadic hyperparathyroidism. 5 6 Loss of parafibromin immunoreactivity serves as a diagnostic marker for CDC73-deficient parathyroid neoplasms. 1 CDC73 pathogenic variants also predispose to renal cancer. 7 Complete surgical resection remains the primary treatment for CDC73-associated parathyroid carcinoma, with 5-year survival rates of 60-93%.