Genome near-haploidization in CDC73-wildtype parathyroid tumors

Parathyroid carcinoma (PC) is most often linked to germline or somatic CDC73 mutations. Previously, we identified three CDC73-wildtype PCs with massive chromosomal losses and genome near-haploidization, with or without endoreduplication/genome doubling - features also seen in rare tumor types such as oncocytic thyroid carcinoma. To assess whether similar alterations occur in other parathyroid neoplasms, we analyzed fourteen parathyroid adenomas (PA; thirteen oncocytic), three atypical parathyroid tumors (APTs; one oncocytic), and one additional PC, the latter four all CDC73-wildtype. Histopathological diagnoses followed the 2022 WHO classification. Genome-wide SNP array analysis was performed to detect copy number variations (CNVs), imbalances and loss of heterozygosity (LOH). APTs and PC underwent somatic mutation analysis, to confirm CDC73-wildtype status. Oncocytic PAs exhibited largely stable genomes, with few or no chromosomal alterations. Patients with chromosomally altered PA had significantly higher preoperative serum calcium levels. In contrast, two of three APTs, and the included PC displayed extensive chromosomal losses and genome near-haploidization. These findings expand the recognized spectrum of chromosomal alterations in CDC73-wildtype parathyroid tumors.