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 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Chetanya
authors.initials: C
authors.lastname: Pandya
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Uzilov
authors.affiliation: Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Bellizzi
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Chun Yee
authors.initials: CY
authors.lastname: Lau
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Aye S
authors.initials: AS
authors.lastname: Moe
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Strahl
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Wissam
authors.initials: W
authors.lastname: Hamou
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Newman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Fink
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Antipin
authors.affiliation: Center for Computational Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Willie
authors.initials: W
authors.lastname: Yu
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Molecular Endocrinology Group, Molecular Pathobiology Research Centre Unit (UIPM) of the Portuguese Institute of Oncology from Lisbon Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Branca M
authors.initials: BM
authors.lastname: Cavaco
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.|Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom.
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sebra
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Shuyu D
authors.initials: SD
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Arnold
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
mesh_terms: D015331:Cohort Studies; D019938:Cyclin D1 / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D010282:Parathyroid Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C530104:CCND1 protein, human; C454900:CDC73 protein, human; C000623307:ADCK1 protein, human; C546842:MTOR protein, human