A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

Autores
Abba, Martín Carlos; Gong,Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matías; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, C. Marcelo
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión aceptada
Descripción
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
Materia
Ciencias Médicas
DCIS
breast cancer
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-nd/4.0/
Repositorio
CIC Digital (CICBA)
Institución
Comisión de Investigaciones Científicas de la Provincia de Buenos Aires
OAI Identificador
oai:digital.cic.gba.gob.ar:11746/6198

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oai_identifier_str oai:digital.cic.gba.gob.ar:11746/6198
network_acronym_str CICBA
repository_id_str 9441
network_name_str CIC Digital (CICBA)
spelling A Molecular Portrait of High-Grade Ductal Carcinoma In SituAbba, Martín CarlosGong,TingLu, YueLee, JaehoZhong, YiLacunza, EzequielButti, MatíasTakata, YokoGaddis, SallyShen, JianjunEstecio, Marcos R.Sahin, Aysegul A.Aldaz, C. MarceloCiencias MédicasDCISbreast cancerDuctal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.AACR Publications2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://digital.cic.gba.gob.ar/handle/11746/6198enginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-15-0506info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/reponame:CIC Digital (CICBA)instname:Comisión de Investigaciones Científicas de la Provincia de Buenos Airesinstacron:CICBA2025-09-29T13:40:01Zoai:digital.cic.gba.gob.ar:11746/6198Institucionalhttp://digital.cic.gba.gob.arOrganismo científico-tecnológicoNo correspondehttp://digital.cic.gba.gob.ar/oai/snrdmarisa.degiusti@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:94412025-09-29 13:40:01.577CIC Digital (CICBA) - Comisión de Investigaciones Científicas de la Provincia de Buenos Airesfalse
dc.title.none.fl_str_mv A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
title A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
spellingShingle A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
Abba, Martín Carlos
Ciencias Médicas
DCIS
breast cancer
title_short A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
title_full A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
title_fullStr A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
title_full_unstemmed A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
title_sort A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
dc.creator.none.fl_str_mv Abba, Martín Carlos
Gong,Ting
Lu, Yue
Lee, Jaeho
Zhong, Yi
Lacunza, Ezequiel
Butti, Matías
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, C. Marcelo
author Abba, Martín Carlos
author_facet Abba, Martín Carlos
Gong,Ting
Lu, Yue
Lee, Jaeho
Zhong, Yi
Lacunza, Ezequiel
Butti, Matías
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, C. Marcelo
author_role author
author2 Gong,Ting
Lu, Yue
Lee, Jaeho
Zhong, Yi
Lacunza, Ezequiel
Butti, Matías
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, C. Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
DCIS
breast cancer
topic Ciencias Médicas
DCIS
breast cancer
dc.description.none.fl_txt_mv Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
description Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
publishDate 2015
dc.date.none.fl_str_mv 2015-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://digital.cic.gba.gob.ar/handle/11746/6198
url https://digital.cic.gba.gob.ar/handle/11746/6198
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-15-0506
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv AACR Publications
publisher.none.fl_str_mv AACR Publications
dc.source.none.fl_str_mv reponame:CIC Digital (CICBA)
instname:Comisión de Investigaciones Científicas de la Provincia de Buenos Aires
instacron:CICBA
reponame_str CIC Digital (CICBA)
collection CIC Digital (CICBA)
instname_str Comisión de Investigaciones Científicas de la Provincia de Buenos Aires
instacron_str CICBA
institution CICBA
repository.name.fl_str_mv CIC Digital (CICBA) - Comisión de Investigaciones Científicas de la Provincia de Buenos Aires
repository.mail.fl_str_mv marisa.degiusti@sedici.unlp.edu.ar
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