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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-10002464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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