@article{a62753bab1c24a06a26844541aa4ef3d,
title = "Genomic profiling reveals mutational landscape in parathyroid carcinomas",
abstract = "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 the CDC73 tumor 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 observed CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. 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.",
author = "Chetanya Pandya and Uzilov, {Andrew V.} and Justin Bellizzi and Lau, {Chun Yee} and Moe, {Aye S.} and Maya Strahl and Wissam Hamou and Newman, {Leah C.} and Fink, {Marc Y.} and Yevgeniy Antipin and Willie Yu and Mark Stevenson and Cavaco, {Branca M.} and Teh, {Bin T.} and Thakker, {Rajesh V.} and Hans Morreau and Schadt, {Eric E.} and Robert Sebra and Li, {Shuyu D.} and Andrew Arnold and Rong Chen",
note = "Funding Information: This work was supported in part by the Murray-Heilig Fund in Molecular Medicine at University of Connecticut School of Medicine, and through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We thank the Genomics Core Facility at the Icahn Institute and Department of Genetics and Genomic Sciences for technical support. MS and RVT are supported by the UK Medical Research Council (MRC) (G1000467) and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme; RVT is a Wellcome Trust Investigator and NIHR Senior Investigator. BMC is supported by iNOVA4Health (UID/ Multi/04462/2013), a program financially supported by Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia/Minist{\'e}rio da Educa{\c c}{\~a}o e Ci{\^e}ncia through national funds and cofunded by FEDER under the PT2020 partnership. Special thanks to Zhongyang Zhang, Maria da Concei{\c c}{\~a}o Pereira, Maria Jo{\~a}o Bugalho, and Valeriano Leite for helpful discussions regarding the manuscript. Publisher Copyright: {\textcopyright} 2017 American Society for Clinical Investigation. All rights reserved.",
year = "2017",
month = mar,
day = "23",
doi = "10.1172/jci.insight.92061",
language = "English",
volume = "2",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "6",
}