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Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was t...

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Autores principales: Pastorino, Lorenza, Dalmasso, Bruna, Allavena, Eleonora, Vanni, Irene, Ugolini, Filippo, Baroni, Gianna, Croce, Michela, Guadagno, Antonio, Cabiddu, Francesco, Andreotti, Virginia, Bruno, William, Zoppoli, Gabriele, Ferrando, Lorenzo, Tanda, Enrica Teresa, Spagnolo, Francesco, Menin, Chiara, Gangemi, Rosaria, Massi, Daniela, Ghiorzo, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786167/
https://www.ncbi.nlm.nih.gov/pubmed/36555667
http://dx.doi.org/10.3390/ijms232416027
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author Pastorino, Lorenza
Dalmasso, Bruna
Allavena, Eleonora
Vanni, Irene
Ugolini, Filippo
Baroni, Gianna
Croce, Michela
Guadagno, Antonio
Cabiddu, Francesco
Andreotti, Virginia
Bruno, William
Zoppoli, Gabriele
Ferrando, Lorenzo
Tanda, Enrica Teresa
Spagnolo, Francesco
Menin, Chiara
Gangemi, Rosaria
Massi, Daniela
Ghiorzo, Paola
author_facet Pastorino, Lorenza
Dalmasso, Bruna
Allavena, Eleonora
Vanni, Irene
Ugolini, Filippo
Baroni, Gianna
Croce, Michela
Guadagno, Antonio
Cabiddu, Francesco
Andreotti, Virginia
Bruno, William
Zoppoli, Gabriele
Ferrando, Lorenzo
Tanda, Enrica Teresa
Spagnolo, Francesco
Menin, Chiara
Gangemi, Rosaria
Massi, Daniela
Ghiorzo, Paola
author_sort Pastorino, Lorenza
collection PubMed
description ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.
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spelling pubmed-97861672022-12-24 Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma Pastorino, Lorenza Dalmasso, Bruna Allavena, Eleonora Vanni, Irene Ugolini, Filippo Baroni, Gianna Croce, Michela Guadagno, Antonio Cabiddu, Francesco Andreotti, Virginia Bruno, William Zoppoli, Gabriele Ferrando, Lorenzo Tanda, Enrica Teresa Spagnolo, Francesco Menin, Chiara Gangemi, Rosaria Massi, Daniela Ghiorzo, Paola Int J Mol Sci Article ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum. MDPI 2022-12-16 /pmc/articles/PMC9786167/ /pubmed/36555667 http://dx.doi.org/10.3390/ijms232416027 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pastorino, Lorenza
Dalmasso, Bruna
Allavena, Eleonora
Vanni, Irene
Ugolini, Filippo
Baroni, Gianna
Croce, Michela
Guadagno, Antonio
Cabiddu, Francesco
Andreotti, Virginia
Bruno, William
Zoppoli, Gabriele
Ferrando, Lorenzo
Tanda, Enrica Teresa
Spagnolo, Francesco
Menin, Chiara
Gangemi, Rosaria
Massi, Daniela
Ghiorzo, Paola
Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title_full Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title_fullStr Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title_full_unstemmed Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title_short Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma
title_sort ataxia-telangiectasia mutated loss of heterozygosity in melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786167/
https://www.ncbi.nlm.nih.gov/pubmed/36555667
http://dx.doi.org/10.3390/ijms232416027
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