{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:14:20Z","timestamp":1784258060095,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003756","name":"Helsinki University Hospital","doi-asserted-by":"publisher","award":["TYH2019254"],"award-info":[{"award-number":["TYH2019254"]}],"id":[{"id":"10.13039\/501100003756","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Finska L\u00e4kares\u00e4llskapet","award":["TYH2019254"],"award-info":[{"award-number":["TYH2019254"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Parathyroid tumors are mostly sporadic but can also occur in familial forms, including different kinds of genetic syndromes with varying phenotypes and penetrance. Recently, somatic mutations of the tumor suppressor gene PRUNE2 were found to be frequent in parathyroid cancer (PC). The germline mutation status of PRUNE2 was investigated in a large cohort of patients with parathyroid tumors from the genetically homogenous Finnish population, 15 of which had PC, 16 atypical parathyroid tumors (APT), and 6 benign parathyroid adenomas (PA). Mutations in previously established hyperparathyroidism-related genes were screened with a targeted gene panel analysis. Nine PRUNE2 germline mutations with a minor allele frequency (MAF) of &lt;0.05 were found in our cohort. Five of these were predicted to be potentially damaging and were identified in two patients with PC, two with APT, and three with PA. The mutational status was not associated with the tumor group nor related to the clinical picture or severity of the disease. Still, the frequent finding of rare germline mutations of PRUNE2 may point to the gene playing a role in the pathogenesis of parathyroid neoplasms.<\/jats:p>","DOI":"10.3390\/cancers15051405","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T02:01:25Z","timestamp":1677117685000},"page":"1405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel PRUNE2 Germline Mutations in Aggressive and Benign Parathyroid Neoplasms"],"prefix":"10.3390","volume":"15","author":[{"given":"Sara","family":"Storvall","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Abdominal Center, University of Helsinki, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eeva","family":"Ryh\u00e4nen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Abdominal Center, University of Helsinki, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-0796","authenticated-orcid":false,"given":"Auli","family":"Karhu","sequence":"additional","affiliation":[{"name":"Department of Applied Tumor Genomics, Research Programs Unit, University of Helsinki, 00290 Helsinki, Finland"},{"name":"Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2428-0161","authenticated-orcid":false,"given":"Camilla","family":"Schalin-J\u00e4ntti","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Abdominal Center, University of Helsinki, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1080\/0284186X.2017.1306103","article-title":"A nationwide study on parathyroid carcinoma","volume":"56","author":"Leijon","year":"2017","journal-title":"Acta Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.jamcollsurg.2014.10.007","article-title":"Modern experience with aggressive parathyroid tumors in a high-volume New England referral center","volume":"220","author":"Quinn","year":"2015","journal-title":"J. Am. Coll. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.beem.2018.12.003","article-title":"Epidemiology of parathyroid disorders","volume":"32","author":"Rao","year":"2018","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1159\/000491039","article-title":"Parathyroid Carcinoma","volume":"51","author":"Cetani","year":"2018","journal-title":"Front. Horm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1359\/jbmr.081018","article-title":"Parathyroid carcinoma","volume":"23","author":"Marcocci","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1136\/jclinpath-2015-203186","article-title":"Clinicopathological correlates of hyperparathyroidism","volume":"68","author":"Duan","year":"2015","journal-title":"J. Clin. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Schulte, K., Talat, N., and Galat, G. (2023). Margin Free Resection Achieves Excellent Long Term Outcomes in Parathyroid Cancer. Cancers, 15.","DOI":"10.3390\/cancers15010199"},{"key":"ref_8","first-page":"80","article-title":"Parathyroid carcinoma: Diagnosis and clinical implications","volume":"31","author":"Duan","year":"2015","journal-title":"Turk. J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s12022-022-09709-1","article-title":"Overview of the 2022 WHO Classification of Parathyroid Tumors","volume":"33","author":"Erickson","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R441","DOI":"10.1530\/ERC-19-0135","article-title":"Atypical parathyroid adenomas: Challenging lesions in the differential diagnosis of endocrine tumors","volume":"26","author":"Cetani","year":"2019","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1210\/jc.2014-1481","article-title":"CDC73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma","volume":"99","author":"Cranston","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1530\/EC-13-0046","article-title":"CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer","volume":"2","author":"Cetani","year":"2013","journal-title":"Endocr. Connect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/hed.23656","article-title":"Molecular profiling in primary hyperparathyroidism","volume":"37","author":"Segiet","year":"2015","journal-title":"Head Neck"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s12022-020-09656-9","article-title":"Genomics and Epigenomics in Parathyroid Neoplasia: From Bench to Surgical Pathology Practice","volume":"32","author":"Juhlin","year":"2021","journal-title":"Endocr. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.beem.2015.09.007","article-title":"Somatic and germline mutations in NETs: Implications for their diagnosis and management","volume":"30","author":"Minnetti","year":"2016","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1210\/js.2018-00043","article-title":"Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways","volume":"3","author":"Clarke","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.beem.2010.01.003","article-title":"Clinical and Molecular Genetics of Parathyroid Neoplasms John","volume":"24","author":"Sharretts","year":"2008","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R53","DOI":"10.1530\/ERC-18-0304","article-title":"Molecular genetic insights into sporadic primary hyperparathyroidism","volume":"26","author":"Brewer","year":"2019","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1359\/jbmr.1999.14.6.878","article-title":"No evidence for mutations in the calcium-sensing receptor gene in sporadic parathyroid adenomas","volume":"14","author":"Cetani","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/modpathol.2010.236","article-title":"Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma","volume":"24","author":"Witteveen","year":"2011","journal-title":"Mod. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1002\/humu.23337","article-title":"Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma","volume":"38","author":"Cardoso","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"P1","DOI":"10.1530\/EJE-19-0316","article-title":"Unmet therapeutic, educational and scientific needs in parathyroid disorders: Consensus statement from the first European Society of Endocrinology Workshop (PARAT)","volume":"181","author":"Bollerslev","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1002\/ijc.33166","article-title":"The genomic profile of parathyroid carcinoma based on whole-genome sequencing","volume":"147","author":"Hu","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E360","DOI":"10.1210\/jc.2014-3238","article-title":"Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion","volume":"100","author":"Yu","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e92061","DOI":"10.1172\/jci.insight.92061","article-title":"Genomic profiling reveals mutational landscape in parathyroid carcinomas","volume":"2","author":"Pandya","year":"2017","journal-title":"JCI Insight"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1038\/sj.onc.1209225","article-title":"Increased expression of proapoptotic BMCC1, a novel gene with the BNIP2 and Cdc42GAP homology (BCH) domain, is associated with favorable prognosis in human neuroblastomas","volume":"25","author":"Machida","year":"2006","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3892\/etm.2021.11092","article-title":"PRUNE2 inhibits progression of colorectal cancer in vitro and in vivo","volume":"23","author":"Li","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8403","DOI":"10.1073\/pnas.1507882112","article-title":"PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3","volume":"112","author":"Salameh","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1515\/cclm-2019-0693","article-title":"Biomarkers for prostate cancer: Prostate-specific antigen and beyond","volume":"58","author":"Duffy","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-3-319-95693-0_2","article-title":"Novel biomarkers for prostate cancer detection and prognosis","volume":"1095","author":"Filella","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153800","DOI":"10.1016\/j.prp.2022.153800","article-title":"A review on the role of PCA3 lncRNA in carcinogenesis with an especial focus on prostate cancer","volume":"231","author":"Khoshbakht","year":"2022","journal-title":"Pathol. Res. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s12687-017-0318-4","article-title":"Genetics in an isolated population like Finland: A different basis for genomic medicine?","volume":"8","author":"Muilu","year":"2017","journal-title":"J. Community Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The Human Genome Browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D988","DOI":"10.1093\/nar\/gkab1049","article-title":"Ensembl 2022","volume":"50","author":"Cunningham","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1038\/s41596-018-0052-3","article-title":"Discovery of potential causative mutations in human coding and noncoding genome with the interactive software BasePlayer","volume":"13","author":"Katainen","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1001\/archsurg.137.6.641","article-title":"Genotype-phenotype analysis in multiple endocrine neoplasia type 1","volume":"137","author":"Kouvaraki","year":"2002","journal-title":"Arch. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1055\/s-2007-970160","article-title":"Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1","volume":"115","author":"Schaaf","year":"2007","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1002\/mgg3.317","article-title":"Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes","volume":"5","author":"DeRycke","year":"2017","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1053\/j.gastro.2015.05.006","article-title":"Genes in Patients with Suspected Lynch Syndrome","volume":"149","author":"Yurgelun","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1200\/JCO.2014.56.5689","article-title":"Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing","volume":"33","author":"Chubb","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cardoso, M., Maia, S., Brand\u00e3o, A., Sahasrabudhe, R., Lott, P., Belter, N., Carvajal-Carmona, L.G., Paulo, P., and Teixeira, M.R. (Br. J. Cancer, 2022). Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene, Br. J. Cancer, online ahead of print.","DOI":"10.1038\/s41416-022-02125-6"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"834362","DOI":"10.3389\/fendo.2022.834362","article-title":"Genetics and Epigenetics of Parathyroid Carcinoma","volume":"13","author":"Marini","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.ajhg.2018.03.003","article-title":"Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland","volume":"102","author":"Martin","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkaa913","article-title":"Pfam: The protein families database in 2021","volume":"49","author":"Mistry","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"77330","DOI":"10.18632\/oncotarget.20473","article-title":"FLNA is implicated in pulmonary neuroendocrine tumors aggressiveness and progression","volume":"8","author":"Vitali","year":"2017","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34880","DOI":"10.1074\/jbc.M100784200","article-title":"Filamin-A Binds to the Carboxyl-terminal Tail of the Calcium-sensing Receptor, an Interaction that Participates in CaR-mediated Activation of Mitogen-activated Protein Kinase","volume":"276","author":"MacLeod","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"34871","DOI":"10.1074\/jbc.M100775200","article-title":"Interaction of the Calcium-sensing Receptor and Filamin, a Potential Scaffolding Protein","volume":"276","author":"Awata","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1530\/JME-16-0184","article-title":"Filamin A is reduced and contributes to the CASR sensitivity in human parathyroid tumors","volume":"58","author":"Mingione","year":"2017","journal-title":"J. Mol. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1530\/EJE-21-0668","article-title":"Filamin A and parafibromin expression in parathyroid carcinoma","volume":"185","author":"Storvall","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4387","DOI":"10.1172\/JCI91191","article-title":"Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer","volume":"126","author":"Rosano","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"151228","DOI":"10.1016\/j.ejcb.2022.151228","article-title":"Adenomatous Polyposis Coli (APC) in cell migration","volume":"101","author":"Fang","year":"2022","journal-title":"Eur. J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"T53","DOI":"10.1530\/ERC-20-0018","article-title":"Thematic review, Hereditary endocrine tumours: Current state-of-the-art New and future perspectives for parathyroid carcinoma","volume":"27","author":"Perrier","year":"2020","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1038\/onc.2017.43","article-title":"Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: Model for the hyperparathyroidism-jaw tumour syndrome","volume":"36","author":"Walls","year":"2017","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1210\/jc.2011-1571","article-title":"Parathyroid carcinoma: A 43-year outcome and survival analysis","volume":"96","author":"Harari","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.surg.2014.05.014","article-title":"Prognostic factors and staging systems in parathyroid cancer: A multicenter cohort study","volume":"156","year":"2014","journal-title":"Surgery"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/5\/1405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:40:02Z","timestamp":1760121602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/5\/1405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,23]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cancers15051405"],"URL":"https:\/\/doi.org\/10.3390\/cancers15051405","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,23]]}}}