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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/32201
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oai:ri.conicet.gov.ar:11336/32201 |
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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 Técnicas2025-09-29T10:31:24Zoai: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:34982025-09-29 10:31:25.283CONICET 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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1844614324594671616 |
score |
13.070432 |