Genomic profiling reveals mutational landscape in parathyroid carcinomas.
Pandya C., Uzilov AV., Bellizzi J., Lau CY., Moe AS., Strahl M., Hamou W., Newman LC., Fink MY., Antipin Y., Yu W., Stevenson M., Cavaco BM., Teh BT., Thakker RV., Morreau H., Schadt EE., Sebra R., Li SD., Arnold A., Chen R.
Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in theCDC73tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observedCCND1amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinaseADCK1. We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments.