Variant-Level Curation and Molecular Context of Therapeutically Relevant Alterations in Parathyroid Carcinoma: A Nationwide C-CAT Analysis in Japan

Introduction: Parathyroid carcinoma (PC) is an ultra-rare malignancy with limited treatment options. Although comprehensive genomic profiling (CGP) has identified recurrent genomic alterations in PC, the pathogenicity and therapeutic relevance of individual variants and their distribution across molecular subgroups remain incompletely characterized. We aimed to characterize the genomic landscape of PC through variant-level pathogenicity curation and molecular subgroup analysis, with a focus on potentially therapeutically relevant alterations. Methods: We conducted a descriptive analysis of patients with pathologically confirmed PC registered in C-CAT, a Japanese nationwide cancer genomics database. Genomic alterations were systematically curated for pathogenicity using OncoKB and manual review of published and functional evidence. Molecular subgroup analyses were performed in patients with evaluable CDC73 status, classified as CDC73-altered, MEN1-altered, or other tumors. Results: Thirty patients were included. Among 373 unique genomic alterations detected, 114 (30.6%) were classified as pathogenic after variant-level curation. CDC73 (43.3%), TP53 (26.7%), and MEN1 (23.3%) were the most frequently altered genes. High tumor mutational burden (≥ 10 mutations/Mb), mismatch repair (MMR), PI3K–AKT–mTOR, and homologous recombination repair (HRR)-related alterations were identified in 23.3%, 16.7%, 23.3%, and 13.3% of patients, respectively. Only 5 of 25 unique HRR-related alterations (20.0%) were retained as pathogenic after curation. Among 29 patients evaluable for molecular subgroup analysis, therapeutically relevant alterations showed distinct distributions across CDC73-altered, MEN1-altered, and other tumors. CDC73 alterations were mutually exclusive with MEN1, TP53, and PI3K–AKT–mTOR pathway alterations, whereas TP53 alterations co-occurred with PI3K–AKT–mTOR pathway alterations. Conclusions: Variant-level pathogenicity curation substantially refined the genomic alterations identified by CGP in PC, particularly among HRR-related genes. Molecular stratification based on CDC73 and MEN1 revealed distinct patterns of therapeutically relevant alterations, highlighting the importance of interpreting CGP findings within disease-specific molecular contexts.