Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis

Autores
Nibeyro, Guadalupe; Baronetto, Verónica Mabel; Nava, Agustín; Girotti, Maria Romina; Prato, Laura; Morón, Gabriel; Fernandez, Elmer Andres
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Advanced melanoma, characterized by its aggressiveness and genomic complexity, demands improved prognostic and therapeutic strategies, particularly for patients with limited response to immune checkpoint blockade (ICB). Gene fusions, proposed as enhancers of tumor immunogenicity through neoantigens, also reflect chromosomal instability, which influences tumor evolution and therapy outcomes. However, their impact on melanoma remains unexplored. By retrospectively analyzing baseline tumors from 222 ICB-treated patients, we found a high tumor fusion burden (TFB-H) correlation with poor RECIST response, reduced overall survival (time-dependent ROC > 0.6, P << 0.01), and increased mortality risk (HR = 2, P < 0.01). TFB-H was found to be strongly associated with chromosomal instability (β = 0.72, P < 0.01), heightened proliferation, and diminished immune cytolytic activity. TFB-H was also linked to poor prognosis and immune impairment in nonadvanced melanoma tumors (n = 441) that have not received ICB treatment. These findings suggest that TFB-H tumors may exhibit an aggressive phenotype insensitive to ICB, probably due to immune evasion caused by intratumoral heterogeneity. Additionally, we identified targetable fusions, such as KIAA1549::BRAF, which represent therapeutic opportunities for advanced melanoma, including novel type II RAF inhibitors with potent activity against kinase fusions. Integrating gene fusion profiling into clinical practice may guide precision medicine strategies to overcome the limitations of ICB in advanced melanoma, offering prognostic insights and expanding therapeutic options, particularly with emerging fusion-specific inhibitors.Significance:The evidence of this work supports the idea that gene fusion profiling may serve as both a prognostic marker and a guide for alternative therapeutic strategies, including targeted fusion inhibitors, in patients less likely to benefit from ICB.
Fil: Nibeyro, Guadalupe. Fundación Para El Progreso de la Medicina; Argentina. Universidad Tecnológica Nacional. Facultad Regional Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Baronetto, Verónica Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; Argentina
Fil: Nava, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Girotti, Maria Romina. Universidad Argentina de la Empresa; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Prato, Laura. Universidad Nacional de Villa María; Argentina
Fil: Morón, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Materia
cancer
melanoma
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/276939
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective AnalysisNibeyro, GuadalupeBaronetto, Verónica MabelNava, AgustínGirotti, Maria RominaPrato, LauraMorón, GabrielFernandez, Elmer Andrescancermelanomahttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Advanced melanoma, characterized by its aggressiveness and genomic complexity, demands improved prognostic and therapeutic strategies, particularly for patients with limited response to immune checkpoint blockade (ICB). Gene fusions, proposed as enhancers of tumor immunogenicity through neoantigens, also reflect chromosomal instability, which influences tumor evolution and therapy outcomes. However, their impact on melanoma remains unexplored. By retrospectively analyzing baseline tumors from 222 ICB-treated patients, we found a high tumor fusion burden (TFB-H) correlation with poor RECIST response, reduced overall survival (time-dependent ROC > 0.6, P << 0.01), and increased mortality risk (HR = 2, P < 0.01). TFB-H was found to be strongly associated with chromosomal instability (β = 0.72, P < 0.01), heightened proliferation, and diminished immune cytolytic activity. TFB-H was also linked to poor prognosis and immune impairment in nonadvanced melanoma tumors (n = 441) that have not received ICB treatment. These findings suggest that TFB-H tumors may exhibit an aggressive phenotype insensitive to ICB, probably due to immune evasion caused by intratumoral heterogeneity. Additionally, we identified targetable fusions, such as KIAA1549::BRAF, which represent therapeutic opportunities for advanced melanoma, including novel type II RAF inhibitors with potent activity against kinase fusions. Integrating gene fusion profiling into clinical practice may guide precision medicine strategies to overcome the limitations of ICB in advanced melanoma, offering prognostic insights and expanding therapeutic options, particularly with emerging fusion-specific inhibitors.Significance:The evidence of this work supports the idea that gene fusion profiling may serve as both a prognostic marker and a guide for alternative therapeutic strategies, including targeted fusion inhibitors, in patients less likely to benefit from ICB.Fil: Nibeyro, Guadalupe. Fundación Para El Progreso de la Medicina; Argentina. Universidad Tecnológica Nacional. Facultad Regional Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Baronetto, Verónica Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; ArgentinaFil: Nava, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Girotti, Maria Romina. Universidad Argentina de la Empresa; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Prato, Laura. Universidad Nacional de Villa María; ArgentinaFil: Morón, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaAmerican Association for Cancer Research2025-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/276939Nibeyro, Guadalupe; Baronetto, Verónica Mabel; Nava, Agustín; Girotti, Maria Romina; Prato, Laura; et al.; Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis; American Association for Cancer Research; Cancer Research Communications; 5; 8; 7-2025; 1332-13432767-9764CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/cancerrescommun/article/doi/10.1158/2767-9764.CRC-25-0204/763914/Evaluating-Gene-Fusions-as-Prognostic-Biomarkersinfo:eu-repo/semantics/altIdentifier/doi/10.1158/2767-9764.CRC-25-0204info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T14:04:34Zoai:ri.conicet.gov.ar:11336/276939instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-12-23 14:04:34.299CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
title Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
spellingShingle Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
Nibeyro, Guadalupe
cancer
melanoma
title_short Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
title_full Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
title_fullStr Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
title_full_unstemmed Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
title_sort Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis
dc.creator.none.fl_str_mv Nibeyro, Guadalupe
Baronetto, Verónica Mabel
Nava, Agustín
Girotti, Maria Romina
Prato, Laura
Morón, Gabriel
Fernandez, Elmer Andres
author Nibeyro, Guadalupe
author_facet Nibeyro, Guadalupe
Baronetto, Verónica Mabel
Nava, Agustín
Girotti, Maria Romina
Prato, Laura
Morón, Gabriel
Fernandez, Elmer Andres
author_role author
author2 Baronetto, Verónica Mabel
Nava, Agustín
Girotti, Maria Romina
Prato, Laura
Morón, Gabriel
Fernandez, Elmer Andres
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv cancer
melanoma
topic cancer
melanoma
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Advanced melanoma, characterized by its aggressiveness and genomic complexity, demands improved prognostic and therapeutic strategies, particularly for patients with limited response to immune checkpoint blockade (ICB). Gene fusions, proposed as enhancers of tumor immunogenicity through neoantigens, also reflect chromosomal instability, which influences tumor evolution and therapy outcomes. However, their impact on melanoma remains unexplored. By retrospectively analyzing baseline tumors from 222 ICB-treated patients, we found a high tumor fusion burden (TFB-H) correlation with poor RECIST response, reduced overall survival (time-dependent ROC > 0.6, P << 0.01), and increased mortality risk (HR = 2, P < 0.01). TFB-H was found to be strongly associated with chromosomal instability (β = 0.72, P < 0.01), heightened proliferation, and diminished immune cytolytic activity. TFB-H was also linked to poor prognosis and immune impairment in nonadvanced melanoma tumors (n = 441) that have not received ICB treatment. These findings suggest that TFB-H tumors may exhibit an aggressive phenotype insensitive to ICB, probably due to immune evasion caused by intratumoral heterogeneity. Additionally, we identified targetable fusions, such as KIAA1549::BRAF, which represent therapeutic opportunities for advanced melanoma, including novel type II RAF inhibitors with potent activity against kinase fusions. Integrating gene fusion profiling into clinical practice may guide precision medicine strategies to overcome the limitations of ICB in advanced melanoma, offering prognostic insights and expanding therapeutic options, particularly with emerging fusion-specific inhibitors.Significance:The evidence of this work supports the idea that gene fusion profiling may serve as both a prognostic marker and a guide for alternative therapeutic strategies, including targeted fusion inhibitors, in patients less likely to benefit from ICB.
Fil: Nibeyro, Guadalupe. Fundación Para El Progreso de la Medicina; Argentina. Universidad Tecnológica Nacional. Facultad Regional Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Baronetto, Verónica Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; Argentina
Fil: Nava, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Girotti, Maria Romina. Universidad Argentina de la Empresa; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Prato, Laura. Universidad Nacional de Villa María; Argentina
Fil: Morón, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Para El Progreso de la Medicina; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
description Advanced melanoma, characterized by its aggressiveness and genomic complexity, demands improved prognostic and therapeutic strategies, particularly for patients with limited response to immune checkpoint blockade (ICB). Gene fusions, proposed as enhancers of tumor immunogenicity through neoantigens, also reflect chromosomal instability, which influences tumor evolution and therapy outcomes. However, their impact on melanoma remains unexplored. By retrospectively analyzing baseline tumors from 222 ICB-treated patients, we found a high tumor fusion burden (TFB-H) correlation with poor RECIST response, reduced overall survival (time-dependent ROC > 0.6, P << 0.01), and increased mortality risk (HR = 2, P < 0.01). TFB-H was found to be strongly associated with chromosomal instability (β = 0.72, P < 0.01), heightened proliferation, and diminished immune cytolytic activity. TFB-H was also linked to poor prognosis and immune impairment in nonadvanced melanoma tumors (n = 441) that have not received ICB treatment. These findings suggest that TFB-H tumors may exhibit an aggressive phenotype insensitive to ICB, probably due to immune evasion caused by intratumoral heterogeneity. Additionally, we identified targetable fusions, such as KIAA1549::BRAF, which represent therapeutic opportunities for advanced melanoma, including novel type II RAF inhibitors with potent activity against kinase fusions. Integrating gene fusion profiling into clinical practice may guide precision medicine strategies to overcome the limitations of ICB in advanced melanoma, offering prognostic insights and expanding therapeutic options, particularly with emerging fusion-specific inhibitors.Significance:The evidence of this work supports the idea that gene fusion profiling may serve as both a prognostic marker and a guide for alternative therapeutic strategies, including targeted fusion inhibitors, in patients less likely to benefit from ICB.
publishDate 2025
dc.date.none.fl_str_mv 2025-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/276939
Nibeyro, Guadalupe; Baronetto, Verónica Mabel; Nava, Agustín; Girotti, Maria Romina; Prato, Laura; et al.; Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis; American Association for Cancer Research; Cancer Research Communications; 5; 8; 7-2025; 1332-1343
2767-9764
CONICET Digital
CONICET
url http://hdl.handle.net/11336/276939
identifier_str_mv Nibeyro, Guadalupe; Baronetto, Verónica Mabel; Nava, Agustín; Girotti, Maria Romina; Prato, Laura; et al.; Evaluating Gene Fusions as Prognostic Biomarkers and Therapeutic Targets in Immune Checkpoint Blockade–Treated Advanced Melanoma: A Retrospective Analysis; American Association for Cancer Research; Cancer Research Communications; 5; 8; 7-2025; 1332-1343
2767-9764
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/cancerrescommun/article/doi/10.1158/2767-9764.CRC-25-0204/763914/Evaluating-Gene-Fusions-as-Prognostic-Biomarkers
info:eu-repo/semantics/altIdentifier/doi/10.1158/2767-9764.CRC-25-0204
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.952241

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