The Genomic Profile Of Parathyroid Carcinoma Based On Whole-Genome Sequencing

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such asCDC73have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole-genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. InactivatingCDC73mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer-related mutations identified in more than one case wereMAF(2/23),NEB(6/23),NCOR1(2/23),TTK(2/23),GRIN3A(4/23),TRIO(2/23),MAP1B(2/23),TJP2(2/23) andFAM20A(2/23). In the seven wild-typeCDC73samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P= .006) andCDC73mutations (P= .022) than in those without these characteristics.PIK3CAloss was found in one sample, which also harboured aCDC73mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer-predisposing mutations werePDE4DIP(15/23),MAP3K1(13/23) andCDC42EP1(10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC.CDC73mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild-typeCDC73harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on theCDC73mutation may help to manage follow-up and therapy for PC patients.