The genomic profile of parathyroid carcinoma based on whole‐genome sequencing

Abstract

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have 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. Inactivating CDC73 mutations 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 were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild‐type CDC73 samples, 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) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer‐predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild‐type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow‐up and therapy for PC patients.

Genomics and Epigenomics in Parathyroid Neoplasia: from Bench to Surgical Pathology Practice

“…Somatic CDC73 gene mutations are the most frequent somatic alteration in parathyroid carcinoma (Table 1, Fig. 2) [79][80][81][82]. These mutations are in general disruptive due to premature truncations or frameshift alterations, alternatively the mutations are of missense nature in conserved regions encoding the nuclear localization signals (NLSs) or the human polymerase-associated factor 1 (hPAF1) complex of the corresponding protein product, termed parafibromin.…”

Parathyroid Carcinoma All-In-One, a Rare Life-Threatening Case With Multiple Systemic Manifestations: Case Report and Review of the Literature

“…Moreover, whole-exome sequencing of PC has been recently performed, identifying mutations in other genes, such as mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2 genes, as well as CCND1 gene amplification. Particularly, alterations in the PI3K/AKT/mTOR pathway can usually be found in sporadic forms ( 11 ). Unfortunately, in the case described here, the patient had no family history of hyperparathyroidism and refused genetic analysis.…”

“…In the presented case, as in other cases described by literature, nuclear medicine imaging techniques, such as MIBI scan and 18 F-FDG PET-CT, were helpful in localizing the mass and predicting malignancy, respectively. Moreover, 11 C-methionine PET-CT and 18 F-Fluorocholine PET-CT may also be used to locate hyperfunctional parathyroid in PC, especially in cases of relapse of the disease or in the occurrence of ectopia (13). Indeed, as for benign parathyroid lesions, PC may potentially develop in several anatomic locations including the mediastinum, the retroor para-esophageal space, intrathymic or intrathyroidal sites, as well as the carotid sheath (14).…”

Patterns and Predictors of Cervical Lymph Node Metastasis in Parathyroid Carcinoma

“…Most of the parafibromin and Ki67 immunohistochemical (IHC) staining results and CDC73 mutation status data were collected from previous studies at our institute [ 24 , 25 , 26 , 27 ]. Some of the IHC results and CDC73 sequencing were supplemented according to our previous studies mentioned above.…”