Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mu...

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Autores principales:	Monica De Luise, Luisa Iommarini, Lorena Marchio, Greta Tedesco, Camelia Alexandra Coadă, Andrea Repaci, Daniela Turchetti, Maria Lucia Tardio, Nunzio Salfi, Uberto Pagotto, Ivana Kurelac, Anna Maria Porcelli, Giuseppe Gasparre
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	mitochondrial DNA mutations familial oncocytic tumors respiratory complexes hyperparathyroidism-jaw tumor syndrome parathyroid cancer Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5b126784dc2b48678f3729341d82e54f
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spelling	oai:doaj.org-article:5b126784dc2b48678f3729341d82e54f2021-11-25T17:08:55ZPathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome10.3390/cells101129202073-4409https://doaj.org/article/5b126784dc2b48678f3729341d82e54f2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2920https://doaj.org/toc/2073-4409While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.Monica De LuiseLuisa IommariniLorena MarchioGreta TedescoCamelia Alexandra CoadăAndrea RepaciDaniela TurchettiMaria Lucia TardioNunzio SalfiUberto PagottoIvana KurelacAnna Maria PorcelliGiuseppe GasparreMDPI AGarticlemitochondrial DNA mutationsfamilial oncocytic tumorsrespiratory complexeshyperparathyroidism-jaw tumor syndromeparathyroid cancerBiology (General)QH301-705.5ENCells, Vol 10, Iss 2920, p 2920 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mitochondrial DNA mutations familial oncocytic tumors respiratory complexes hyperparathyroidism-jaw tumor syndrome parathyroid cancer Biology (General) QH301-705.5
spellingShingle	mitochondrial DNA mutations familial oncocytic tumors respiratory complexes hyperparathyroidism-jaw tumor syndrome parathyroid cancer Biology (General) QH301-705.5 Monica De Luise Luisa Iommarini Lorena Marchio Greta Tedesco Camelia Alexandra Coadă Andrea Repaci Daniela Turchetti Maria Lucia Tardio Nunzio Salfi Uberto Pagotto Ivana Kurelac Anna Maria Porcelli Giuseppe Gasparre Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
description	While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.
format	article
author	Monica De Luise Luisa Iommarini Lorena Marchio Greta Tedesco Camelia Alexandra Coadă Andrea Repaci Daniela Turchetti Maria Lucia Tardio Nunzio Salfi Uberto Pagotto Ivana Kurelac Anna Maria Porcelli Giuseppe Gasparre
author_facet	Monica De Luise Luisa Iommarini Lorena Marchio Greta Tedesco Camelia Alexandra Coadă Andrea Repaci Daniela Turchetti Maria Lucia Tardio Nunzio Salfi Uberto Pagotto Ivana Kurelac Anna Maria Porcelli Giuseppe Gasparre
author_sort	Monica De Luise
title	Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
title_short	Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
title_full	Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
title_fullStr	Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
title_full_unstemmed	Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome
title_sort	pathogenic mitochondrial dna mutation load inversely correlates with malignant features in familial oncocytic parathyroid tumors associated with hyperparathyroidism-jaw tumor syndrome
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5b126784dc2b48678f3729341d82e54f
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Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome

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