Integrated single-cell and genomic analysis reveals CDC73-centered malignant reprogramming in parathyroid carcinoma

ABSTRACT: Parathyroid carcinoma (PC) is a rare but aggressive endocrine malignancy with limited therapeutic options, and although CDC73 alterations are a major genetic event in PC, their relationships to tumor-cell states and microenvironmental remodeling remain incompletely defined. To address this, we performed integrated whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq) on parathyroid tumors from four patients with PC and four with parathyroid adenoma (PA) to define cell type-specific transcriptional programs and tumor microenvironmental features according to histology and CDC73 status. WES identified CDC73 alterations in two of four carcinomas, both showing evidence of biallelic inactivation. Compared with PA, PC showed relative expansion of endocrine tumor cells, depletion of endothelial cells, enrichment of cell-cycle programs, activation of PI3K/MAPK signaling, and suppression of p53 activity, with these transcriptional changes following a gradient from PA to CDC73-wild-type PC to CDC73-mutant PC. Within endocrine cells, CDC73-mutant carcinomas were distinguished by reduced endocrine-lineage features, decreased ERBB4 and CASR expression, increased UCHL1 and WT1 expression, and selective activation of MYC regulons. Within the tumor microenvironment, carcinomas were characterized by enrichment of MMP11-positive cancer-associated fibroblasts and fibroblast-driven collagen–integrin signaling, whereas CDC73-mutant tumors additionally exhibited preferential accumulation of regulatory T cells and MARCO-positive protumor macrophages, along with BTLA-associated Treg–macrophage interactions. Overall, integrated genomic and single-cell profiling reveals that parathyroid carcinoma comprises coupled endocrine-cell reprogramming and stromal/immune remodeling, with CDC73 mutation defining a distinct malignant state, supporting CDC73-based molecular stratification and nominating tumor-intrinsic MYC programs, and immunosuppressive myeloid-lymphoid crosstalk as candidate biomarkers and therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324920 | GEO | 2026/06/01

REPOSITORIES: GEO