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Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to...

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Autores principales: Vanni, Irene, Pastorino, Lorenza, Tanda, Enrica Teresa, Andreotti, Virginia, Dalmasso, Bruna, Solari, Nicola, Mascherini, Matteo, Cabiddu, Francesco, Guadagno, Antonio, Coco, Simona, Allavena, Eleonora, Bruno, William, Pietra, Gabriella, Croce, Michela, Gangemi, Rosaria, Piana, Michele, Zoppoli, Gabriele, Ferrando, Lorenzo, Spagnolo, Francesco, Queirolo, Paola, Ghiorzo, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002464/
https://www.ncbi.nlm.nih.gov/pubmed/36901733
http://dx.doi.org/10.3390/ijms24054302
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author Vanni, Irene
Pastorino, Lorenza
Tanda, Enrica Teresa
Andreotti, Virginia
Dalmasso, Bruna
Solari, Nicola
Mascherini, Matteo
Cabiddu, Francesco
Guadagno, Antonio
Coco, Simona
Allavena, Eleonora
Bruno, William
Pietra, Gabriella
Croce, Michela
Gangemi, Rosaria
Piana, Michele
Zoppoli, Gabriele
Ferrando, Lorenzo
Spagnolo, Francesco
Queirolo, Paola
Ghiorzo, Paola
author_facet Vanni, Irene
Pastorino, Lorenza
Tanda, Enrica Teresa
Andreotti, Virginia
Dalmasso, Bruna
Solari, Nicola
Mascherini, Matteo
Cabiddu, Francesco
Guadagno, Antonio
Coco, Simona
Allavena, Eleonora
Bruno, William
Pietra, Gabriella
Croce, Michela
Gangemi, Rosaria
Piana, Michele
Zoppoli, Gabriele
Ferrando, Lorenzo
Spagnolo, Francesco
Queirolo, Paola
Ghiorzo, Paola
author_sort Vanni, Irene
collection PubMed
description Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600− subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.
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spelling pubmed-100024642023-03-11 Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting Vanni, Irene Pastorino, Lorenza Tanda, Enrica Teresa Andreotti, Virginia Dalmasso, Bruna Solari, Nicola Mascherini, Matteo Cabiddu, Francesco Guadagno, Antonio Coco, Simona Allavena, Eleonora Bruno, William Pietra, Gabriella Croce, Michela Gangemi, Rosaria Piana, Michele Zoppoli, Gabriele Ferrando, Lorenzo Spagnolo, Francesco Queirolo, Paola Ghiorzo, Paola Int J Mol Sci Article Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600− subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively. MDPI 2023-02-21 /pmc/articles/PMC10002464/ /pubmed/36901733 http://dx.doi.org/10.3390/ijms24054302 Text en © 2023 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
Vanni, Irene
Pastorino, Lorenza
Tanda, Enrica Teresa
Andreotti, Virginia
Dalmasso, Bruna
Solari, Nicola
Mascherini, Matteo
Cabiddu, Francesco
Guadagno, Antonio
Coco, Simona
Allavena, Eleonora
Bruno, William
Pietra, Gabriella
Croce, Michela
Gangemi, Rosaria
Piana, Michele
Zoppoli, Gabriele
Ferrando, Lorenzo
Spagnolo, Francesco
Queirolo, Paola
Ghiorzo, Paola
Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title_full Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title_fullStr Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title_full_unstemmed Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title_short Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting
title_sort whole-exome sequencing and cfdna analysis uncover genetic determinants of melanoma therapy response in a real-world setting
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002464/
https://www.ncbi.nlm.nih.gov/pubmed/36901733
http://dx.doi.org/10.3390/ijms24054302
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