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The authors hypothesize iChr12p-mediated disruption of vitamin D metabolism through altered FGF23 and PTHLH expression, affecting hormone catabolism and VDR activity, and conclude that intratesticular vitamin D homeostasis is extensively 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role does isochromosome 12p play in testicular cancer?","Question",{"text":63,"@type":64},"Isochromosome 12p (iChr12p) is reported as a typical marker in almost all invasive testicular cancers and is associated with increased gene dosage on chromosome 12p.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How did the study distinguish seminomas from non-seminomatous tumors?",{"text":68,"@type":64},"The authors used TCGA RNAseq and clustering of VDR expression signatures, and also applied TCGA mRNA expression of vitamin D anabolic and catabolic enzymes plus feedback regulators to differentiate tumor types.",{"name":70,"@type":61,"acceptedAnswer":71},"What mechanism is proposed for how iChr12p may affect vitamin D metabolism?",{"text":72,"@type":64},"The hypothesis is that iChr12p formation disturbs vitamin D metabolism via increased FGF23 and PTHLH expression, where FGF23 represses CYP27B1 and PTHLH can drive hypercalcemia by inactivating 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Törzsök 1, Jasper Van Goubergen 2, Martin Pichler 3,4, Renate Pichler 5, *,† and Fr²d²ric R. Santer 2, *,†  \nCitation: Törzsök, P.; Van Goubergen, J.; Pichler, M.; Pichler, R.; Santer, F.R. Isochromosome 12p Formation Regulates Vitamin D Metabolism in Testicular Cancer. Nutrients 2023, 15, 2384. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)nu15102384  \nAcademic Editors: Jose  \nM. Martin-Moreno and Alejandro Mart½n-Gorgojo  \nReceived: 13 April 2023  \nRevised: 17 May 2023  \nAccepted: 18 May 2023  \nPublished: 19 May 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Urology and Andrology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; [p.toerzsoek@salk.at](p.toerzsoek@salk.at)  \n2 Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [jasper.van-goubergen@i-med.ac.at](jasper.van-goubergen@i-med.ac.at)  \n3 Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria; [martin.pichler@medunigraz.at](martin.pichler@medunigraz.at)  \n4 Translational Oncology, University Hospital of Augsburg, 86156 Augsburg, Germany  \n5 Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, 6020 Innsbruck, Austria  \n* Correspondence: [renate.pichler@i-med.ac.at](renate.pichler@i-med.ac.at) (R.P.); [frederic.santer@i-med.ac.at](frederic.santer@i-med.ac.at) (F.R.S.)† These authors contributed equally to this work.  \nAbstract: Isochromosome 12p (iChr12p) is typical in almost all invasive testicular cancers. Increased copy number of genes on 12p is associated with the development of a clinically manifest tumor; however, the causative genes have not yet been identified. Chromosome 12 harbors many genes involved in Vitamin D metabolism. RNAseq analysis of Vitamin D receptor (VDR) genes from the TCGA cohort revealed that clustering of VDR expression signatures could differentiate between pure seminomas and non-seminomatous germ cell tumors (NSGCT) . Using TCGA mRNA expression of anabolic (CYP2R1, CYP27A1 and CYP27B1) and catabolic (CYP24A1) Vitamin D enzymes, positive (PTHLH, IFNG, and TNF) and negative (FGF23) feedback regulators could also clearly distinguish between pure seminomas and NSGCT. We hypothesize that the regulation of Vitamin D metabolism might be disturbed through iChr12p formation, influencing testicular carcinogenesis via increased FGF23 and PTHLH expression. While FGF23 represses CYP27B1 and activates catabolism of active hormone, increased PTHLH secretion can lead to hypercalcemia via inactivation of VDR. In conclusion, testicular cancer is associated with extensive modifications in intratesticular Vitamin D homeostasis. Further research is needed to clarify whether Vitamin D deficiency causes the formation of iChr12p and whether Vitamin D deficiency via iChr12p genomic aberration is involved in testicular carcinogenesis.  \nKeywords: testicular cancer; isochromosome 12p; Vitamin D; incidence; carcinogenesis; microlithiasis  \n1. Introduction  \nTesticular germ cell tumor (TGCT) is the most commonly developed cancer among men aged between 15 and 40 years, accounting for 5% of urological tumors, with 3 to 10 cases per 100,000 males/per year recorded in Western countries [1]. Epidemiological risk factors for the development of TGCT include testicular dysgenesis syndrome, hypospadias, decreased spermatogenesis and impaired fertility or disorders of sex development, family history of TGCT among first-degree relatives and the pr","cbCailpQElvUoKla","https://ap.wps.com/l/cbCailpQElvUoKla","pdf",3350908,"English","# Abstract\n# Keywords\n# 1. Introduction\n## Epidemiology and risk factors of TGCT\n## Genetic marker iChr12p in invasive disease\n## Geographic and seasonal incidence patterns\n## Vitamin D biology and the VDR pathway","[{\"question\":\"What role does isochromosome 12p play in testicular cancer?\",\"answer\":\"Isochromosome 12p (iChr12p) is reported as a typical marker in almost all invasive testicular cancers and is associated with increased gene dosage on chromosome 12p.\"},{\"question\":\"How did the study distinguish seminomas from non-seminomatous tumors?\",\"answer\":\"The authors used TCGA RNAseq and clustering of VDR expression signatures, and also applied TCGA mRNA expression of vitamin D anabolic and catabolic enzymes plus feedback regulators to differentiate tumor types.\"},{\"question\":\"What mechanism is proposed for how iChr12p may affect vitamin D metabolism?\",\"answer\":\"The hypothesis is that iChr12p formation disturbs vitamin D metabolism via increased FGF23 and PTHLH expression, where FGF23 represses CYP27B1 and PTHLH can drive hypercalcemia by inactivating VDR.\"}]","Isochromosome 12p Formation Regulates Vitamin D Metabolism in Testicular Cancer - Academic Article | PDF",1790271384]