DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations

Autores
Marzese, Diego Matías; Scolyer, Richard A.; Roque Moreno, Maria; Vargas Roig, Laura Maria; Huynh, Jamie L.; Wilmott, James S.; Murali, Rajmohan; Buckland, Michael E.; Barkhoudarian, Garni; Thompson, John F.; Morton, Donald L.; Kelly, Daniel F.; Hoon, Dave S. B.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
Fil: Marzese, Diego Matías. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Scolyer, Richard A.. Melanoma Institute Australia; Australia. Royal Prince Alfred Hospital; Australia. University of Sydney; Australia
Fil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Huynh, Jamie L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Wilmott, James S.. University of Sydney; Australia. Melanoma Institute Australia; Australia
Fil: Murali, Rajmohan. Memorial Sloan-Kettering Cancer Center; Estados Unidos
Fil: Buckland, Michael E.. University of Sydney; Australia. Royal Prince Alfred Hospital; Australia
Fil: Barkhoudarian, Garni. Saint John's Health Center; Estados Unidos
Fil: Thompson, John F.. Royal Prince Alfred Hospital; Australia. University of Sydney; Australia
Fil: Morton, Donald L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Kelly, Daniel F.. Saint John's Health Center; Estados Unidos
Fil: Hoon, Dave S. B.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Materia
Cancer Progression
Gene Deletion
Genome-Wide Dna Methylation
Melanoma Brain Metastasis
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:11336/32201
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/32201
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterationsMarzese, Diego MatíasScolyer, Richard A.Roque Moreno, MariaVargas Roig, Laura MariaHuynh, Jamie L.Wilmott, James S.Murali, RajmohanBuckland, Michael E.Barkhoudarian, GarniThompson, John F.Morton, Donald L.Kelly, Daniel F.Hoon, Dave S. B.Cancer ProgressionGene DeletionGenome-Wide Dna MethylationMelanoma Brain Metastasishttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.Fil: Marzese, Diego Matías. John Wayne Cancer Institute. Department of Molecular Oncology; Estados UnidosFil: Scolyer, Richard A.. Melanoma Institute Australia; Australia. Royal Prince Alfred Hospital; Australia. University of Sydney; AustraliaFil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Huynh, Jamie L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados UnidosFil: Wilmott, James S.. University of Sydney; Australia. Melanoma Institute Australia; AustraliaFil: Murali, Rajmohan. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Buckland, Michael E.. University of Sydney; Australia. Royal Prince Alfred Hospital; AustraliaFil: Barkhoudarian, Garni. Saint John's Health Center; Estados UnidosFil: Thompson, John F.. Royal Prince Alfred Hospital; Australia. University of Sydney; AustraliaFil: Morton, Donald L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados UnidosFil: Kelly, Daniel F.. Saint John's Health Center; Estados UnidosFil: Hoon, Dave S. B.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados UnidosOxford University Press2014-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/32201Marzese, Diego Matías; Scolyer, Richard A.; Roque Moreno, Maria; Vargas Roig, Laura Maria; Huynh, Jamie L.; et al.; DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations; Oxford University Press; Neuro-oncology; 16; 11; 6-2014; 1499-15091522-85171523-5866CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/neuro-oncology/article/16/11/1499/2508988info:eu-repo/semantics/altIdentifier/doi/10.1093/neuonc/nou107info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201072/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:03:51Zoai:ri.conicet.gov.ar:11336/32201instacron: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:34982025-10-22 12:03:51.444CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
title DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
spellingShingle DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
Marzese, Diego Matías
Cancer Progression
Gene Deletion
Genome-Wide Dna Methylation
Melanoma Brain Metastasis
title_short DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
title_full DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
title_fullStr DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
title_full_unstemmed DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
title_sort DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations
dc.creator.none.fl_str_mv Marzese, Diego Matías
Scolyer, Richard A.
Roque Moreno, Maria
Vargas Roig, Laura Maria
Huynh, Jamie L.
Wilmott, James S.
Murali, Rajmohan
Buckland, Michael E.
Barkhoudarian, Garni
Thompson, John F.
Morton, Donald L.
Kelly, Daniel F.
Hoon, Dave S. B.
author Marzese, Diego Matías
author_facet Marzese, Diego Matías
Scolyer, Richard A.
Roque Moreno, Maria
Vargas Roig, Laura Maria
Huynh, Jamie L.
Wilmott, James S.
Murali, Rajmohan
Buckland, Michael E.
Barkhoudarian, Garni
Thompson, John F.
Morton, Donald L.
Kelly, Daniel F.
Hoon, Dave S. B.
author_role author
author2 Scolyer, Richard A.
Roque Moreno, Maria
Vargas Roig, Laura Maria
Huynh, Jamie L.
Wilmott, James S.
Murali, Rajmohan
Buckland, Michael E.
Barkhoudarian, Garni
Thompson, John F.
Morton, Donald L.
Kelly, Daniel F.
Hoon, Dave S. B.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cancer Progression
Gene Deletion
Genome-Wide Dna Methylation
Melanoma Brain Metastasis
topic Cancer Progression
Gene Deletion
Genome-Wide Dna Methylation
Melanoma Brain Metastasis
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
Fil: Marzese, Diego Matías. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Scolyer, Richard A.. Melanoma Institute Australia; Australia. Royal Prince Alfred Hospital; Australia. University of Sydney; Australia
Fil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Huynh, Jamie L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Wilmott, James S.. University of Sydney; Australia. Melanoma Institute Australia; Australia
Fil: Murali, Rajmohan. Memorial Sloan-Kettering Cancer Center; Estados Unidos
Fil: Buckland, Michael E.. University of Sydney; Australia. Royal Prince Alfred Hospital; Australia
Fil: Barkhoudarian, Garni. Saint John's Health Center; Estados Unidos
Fil: Thompson, John F.. Royal Prince Alfred Hospital; Australia. University of Sydney; Australia
Fil: Morton, Donald L.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
Fil: Kelly, Daniel F.. Saint John's Health Center; Estados Unidos
Fil: Hoon, Dave S. B.. John Wayne Cancer Institute. Department of Molecular Oncology; Estados Unidos
description Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
publishDate 2014
dc.date.none.fl_str_mv 2014-06
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/11336/32201
Marzese, Diego Matías; Scolyer, Richard A.; Roque Moreno, Maria; Vargas Roig, Laura Maria; Huynh, Jamie L.; et al.; DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations; Oxford University Press; Neuro-oncology; 16; 11; 6-2014; 1499-1509
1522-8517
1523-5866
CONICET Digital
CONICET
url http://hdl.handle.net/11336/32201
identifier_str_mv Marzese, Diego Matías; Scolyer, Richard A.; Roque Moreno, Maria; Vargas Roig, Laura Maria; Huynh, Jamie L.; et al.; DNA methylation and gene deletion analysisof brain metastases in melanoma patients identifies mutually exclusive molecular alterations; Oxford University Press; Neuro-oncology; 16; 11; 6-2014; 1499-1509
1522-8517
1523-5866
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://academic.oup.com/neuro-oncology/article/16/11/1499/2508988
info:eu-repo/semantics/altIdentifier/doi/10.1093/neuonc/nou107
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201072/
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 Oxford University Press
publisher.none.fl_str_mv Oxford University Press
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 12.982451

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