Endocrine Abstracts

Atypical parathyroid tumors (APT) represent parathyroid neoplasms characterized by an uncertain malignant potential due to the presence of histological features typical of parathyroid carcinomas (PC), without infiltration of surrounding tissues. The diagnosis of APT can be very challenging. Surgery is often curative but patients with APT may experience recurrence. Although the molecular landscape of benign parathyroid adenoma (PA) and PC has been explored, only few cases of APT have been included in low-throughput genomic analyses. We performed the first study investigating the whole exome sequencing (WES) of APT cases to characterize molecular signatures and deregulated pathways. Tumor specimens having a histopathological diagnosis of APT were collected from 16 Italian patients treated surgically for sporadic PHPT. DNA from tumors and matched peripheral blood were analyzed by WES on an Illumina HiSeq3000 instrument. A total of 192 somatic nonsynonymous variants were found. The median number of protein-altering mutations in APT was 9, lower than previously found in PC and higher than PA. No genes altered in more than 2 samples were observed. The most frequently mutated genes were BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, OR1S1. Seventeen mutated genes are reported in the Cancer Gene Census (ATM, BCOR, CDC73, DNM2, EZH2, GPC3, MED12, MEN1, MTOR, PIK3CA, PIK3CB, RANBP2, RNF213, UBR5, ZNF521, FAT3, MUC16 ). The gene network created with STRING had significantly more interactions than expected by chance (P=0.001). The most consistent hub genes were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB and UBR5. The PI3K/AKT/mTOR and Wnt signaling as well as the extracellular matrix organization were the main deregulated pathways. Interestingly, the study revealed variants in genes (MEN1, CDC73, EZH2, PIK3CA, MTOR ) previously reported as established or putative/candidate driver genes in PA and/or PC. Only the APT sample CDC73 mutation-positive was significantly enriched in APOBEC mutations. In conclusion, we provide evidence that APT might represent an intermediate entity between PA and PC even from a genomic point of view. It should be clarified if the rare occurrence of somatic CDC73 mutations in APT is associated with higher risk of recurrence, although all patients of our series were cured after >6 years of average follow-up. This study also pinpointed the role of key epigenetic modifier genes (BCOR, KDM2A, CHD4, MBD4, EZH2 ) involved in chromatin remodeling, DNA and histone methylation. These mechanisms take on a role of growing interest in cancer development and offer promise for the development of novel epigenome-targeted therapies.