{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:19:55Z","timestamp":1784557195108,"version":"3.55.0"},"reference-count":48,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:p>The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium-sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome.<\/jats:p>","DOI":"10.1530\/erc-17-0470","type":"journal-article","created":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T20:20:12Z","timestamp":1519417212000},"page":"407-420","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":9,"title":["Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT"],"prefix":"10.1530","volume":"25","author":[{"given":"James","family":"Koh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce A","family":"Hogue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanziana A","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall P","family":"Scheri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e8l\u00e9ne","family":"Fradin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Corcoran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Sosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref321","first-page":"10","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","year":"2011","journal-title":"Bioinformatics in Action"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1210\/me.2003-0300","article-title":"The Rab-binding protein Noc2 is associated with insulin-containing secretory granules and is essential for pancreatic beta-cell exocytosis","volume":"18","year":"2004","journal-title":"Molecular Endocrinology"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1210\/me.2010-0277","article-title":"Regulator of G-protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor","volume":"25","year":"2011","journal-title":"Molecular Endocrinology"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-94-007-2888-2_5","article-title":"Signaling through the extracellular calcium-sensing receptor (CaSR)","volume":"740","year":"2012","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref361","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1152\/physrev.00015.2002","article-title":"Molecular physiology of P2X receptors","volume":"82","year":"2002","journal-title":"Physiological Reviews"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1007\/s00125-010-1773-1","article-title":"Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats","volume":"53","year":"2010","journal-title":"Diabetologia"},{"key":"ref341","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0002-9440(10)63321-4","article-title":"Molecular classification of parathyroid neoplasia by gene expression profiling","volume":"165","year":"2004","journal-title":"American Journal of Pathology"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","year":"2013","journal-title":"Bioinformatics"},{"key":"ref421","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/cen.12479","article-title":"Changes in parathyroid proteome in patients with primary hyperparathyroidism due to sporadic parathyroid adenomas","volume":"81","year":"2014","journal-title":"Clinical Endocrinology"},{"key":"ref191","first-page":"3481","article-title":"Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism","volume":"82","year":"1997","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1074\/jbc.M113.523654","article-title":"A role for peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) in the regulation of cardiac mitochondrial phospholipid biosynthesis","volume":"289","year":"2014","journal-title":"Journal of Biological Chemistry"},{"key":"ref381","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrm3775","article-title":"Organization and execution of the epithelial polarity programme","volume":"15","year":"2014","journal-title":"Nature Reviews: Molecular Cell Biology"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.tibs.2009.10.008","article-title":"The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling","volume":"35","year":"2010","journal-title":"Trends in Biochemical Sciences"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nmeth.3252","article-title":"Orchestrating high-throughput genomic analysis with bioconductor","volume":"12","year":"2015","journal-title":"Nature Methods"},{"key":"ref451","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.metabol.2017.06.004","article-title":"Impaired calcium sensing distinguishes primary hyperparathyroidism (PHPT) patients with low bone mineral density","volume":"74","year":"2017","journal-title":"Metabolism"},{"key":"ref311","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","year":"2014","journal-title":"Genome Biology"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1089\/cmb.2012.0283","article-title":"Calculating sample size estimates for RNA sequencing data","volume":"20","year":"2013","journal-title":"Journal of Computational Biology"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"e0126213","DOI":"10.1371\/journal.pone.0126213","article-title":"Adducin is involved in endothelial barrier stabilization","volume":"10","year":"2015","journal-title":"PLoS ONE"},{"key":"ref61","first-page":"1165","article-title":"The control of the false discovery rate in multiple testing under dependency","volume":"29","year":"2001","journal-title":"Annals of Statistics"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.2174\/1871527314666150326000018","article-title":"Peroxisome proliferator activated receptor gamma coactivator 1 alpha: an emerging target for neuroprotection in Parkinson\u2019s disease","volume":"14","year":"2015","journal-title":"CNS and Neurological Disorders \u2013 Drug Targets"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/jcmm.12732","article-title":"Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism","volume":"20","year":"2016b","journal-title":"Journal of Cellular and Molecular Medicine"},{"key":"ref261","doi-asserted-by":"crossref","first-page":"e0161134","DOI":"10.1371\/journal.pone.0161134","article-title":"A novel ex vivo method for visualizing live-cell calcium response behavior in intact human tumors","volume":"11","year":"2016a","journal-title":"PLoS ONE"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate \u2013 a practical and powerful approach to multiple testing","volume":"57","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B: Methodological"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.beem.2013.03.003","article-title":"The calcium sensing receptor life cycle: trafficking, cell surface expression, and degradation","volume":"27","year":"2013","journal-title":"Best Practice and Research: Clinical Endocrinology and Metabolism"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"5438","DOI":"10.1074\/jbc.M007699200","article-title":"Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling","volume":"276","year":"2001","journal-title":"Journal of Biological Chemistry"},{"key":"ref151","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1210\/jc.2012-1743","article-title":"WilliamsCLiftonRPCarlingT Identification of somatic mutations in parathyroid tumors using whole - exome sequencing of and https org","year":"2012","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref411","first-page":"190","article-title":"The calcium-sensing receptor and integrins in cellular differentiation and migration","volume":"7","year":"2016","journal-title":"Frontiers in Physiology"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1016\/j.bbamcr.2012.12.011","article-title":"Calcium sensing receptor signalling in physiology and cancer","volume":"1833","year":"2013","journal-title":"Biochimica et Biophysica Acta"},{"key":"ref371","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/bs.pmbts.2015.02.006","article-title":"Calcium-sensing receptor: trafficking, endocytosis, recycling, and importance of interacting proteins","volume":"132","year":"2015","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1046\/j.1365-2265.2000.00933.x","article-title":"Calcium-sensing receptor expression and signalling in human parathyroid adenomas and primary hyperplasia","volume":"52","year":"2000","journal-title":"Clinical Endocrinology"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nbt1385","article-title":"Direct multiplexed measurement of gene expression with color-coded probe pairs","volume":"26","year":"2008","journal-title":"Nature Biotechnology"},{"key":"ref331","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","year":"2003","journal-title":"Nature Genetics"},{"key":"ref351","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.bbalip.2007.04.002","article-title":"The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking","volume":"1771","year":"2007","journal-title":"Biochimica et Biophysica Acta"},{"key":"ref401","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/geno.1999.5864","article-title":"Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3 medulloblastoma tumor suppressor locus","volume":"59","year":"1999","journal-title":"Genomics"},{"key":"ref241","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1093\/nar\/gkr895","article-title":"an integrative resource for genome - scale data from non - vertebrate species https org","author":"Ensembl","year":"2012","journal-title":"genomes Nucleic Acids Research"},{"key":"ref391","doi-asserted-by":"crossref","first-page":"14925","DOI":"10.1074\/jbc.M113.527127","article-title":"Adducin is required for desmosomal cohesion in keratinocytes","volume":"289","year":"2014","journal-title":"Journal of Biological Chemistry"},{"key":"ref471","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1161\/ATVBAHA.112.301019","article-title":"Peroxisome proliferator-activated receptor gamma coactivator-1alpha is a central negative regulator of vascular senescence","volume":"33","year":"2013","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"ref461","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1359\/JBMR.050910","article-title":"Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993\u20132001: an update on the changing epidemiology of the disease","volume":"21","year":"2006","journal-title":"Journal of Bone and Mineral Research"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1056\/NEJMcp032200","article-title":"Clinical practice. Asymptomatic primary hyperparathyroidism","volume":"350","year":"2004","journal-title":"New England Journal of Medicine"},{"key":"ref111","first-page":"4789","article-title":"Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism","volume":"85","year":"2000","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref431","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1093\/bioinformatics\/bts188","article-title":"NanoStringNorm: an extensible R package for the pre-processing of NanoString mRNA and miRNA data","volume":"28","year":"2012","journal-title":"Bioinformatics"},{"key":"ref441","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1002\/art.39182","article-title":"Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor gamma coactivator 1alpha","volume":"67","year":"2015","journal-title":"Arthritis and Rheumatology"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1039\/C0MB00191K","article-title":"A proteomic approach to study parathyroid glands","volume":"7","year":"2011","journal-title":"Molecular Biosystems"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"197","DOI":"10.21873\/cgp.20031","article-title":"Proteomics analysis of tissue samples reveals changes in mitochondrial protein levels in parathyroid hyperplasia over adenoma","volume":"14","year":"2017","journal-title":"Cancer Genomics Proteomics"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/0169-6009(92)92325-","article-title":"Molecular pathogenesis of primary hyperparathyroidism of and Supplement https org","volume":"17","year":"2002","journal-title":"Journal Bone Mineral Research"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014a Python framework to work with high-throughput sequencing data.","volume":"31","year":"2015","journal-title":"Bioinformatics"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"621","DOI":"10.3892\/ol.2016.4623","article-title":"Molecular pathways associated with transcriptional alterations in hyperparathyroidism","volume":"12","year":"2016","journal-title":"Oncology Letters"},{"key":"ref481","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/ki.2012.188","article-title":"Activation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury","volume":"82","year":"2012","journal-title":"Kidney International"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/25\/4\/ERC-17-0470.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1530\/ERC-17-0470","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:54:39Z","timestamp":1784555679000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/25\/4\/407-420\/25241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4]]},"references-count":48,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.1530\/erc-17-0470","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4]]}}}