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, Matias; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, Marcelo
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
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 ERBB2þ) displayed signatures characteristic of activated Treg cells (CD4þ/CD25þ/FOXP3þ) and CTLA4þ/CD86þ 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.
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gong, Ting. University Of Texas; Estados Unidos
Fil: Lu, Yue. University Of Texas; Estados Unidos
Fil: Lee, Jaeho. University Of Texas; Estados Unidos
Fil: Zhong, Yi. University Of Texas; Estados Unidos
Fil: Lacunza, Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Butti, Matias. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Takata, Yoko. University Of Texas; Estados Unidos
Fil: Gaddis, Sally. University Of Texas; Estados Unidos
Fil: Shen, Jianjun. University Of Texas; Estados Unidos
Fil: Estecio, Marcos R.. University Of Texas; Estados Unidos
Fil: Sahin, Aysegul A.. University Of Texas; Estados Unidos
Fil: Aldaz, Marcelo. University Of Texas; Estados Unidos
Materia
Ductal Carcinoma in Situ
Breast Cancer
Gene Expresssion
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:11336/13711
Acceder
id CONICETDig_97e65c80f78386e757e69c419a7cbc8f
oai_identifier_str oai:ri.conicet.gov.ar:11336/13711
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A molecular portrait of high-grade Ductal Carcinoma in situAbba, Martín CarlosGong, TingLu, YueLee, JaehoZhong, YiLacunza, EzequielButti, MatiasTakata, YokoGaddis, SallyShen, JianjunEstecio, Marcos R.Sahin, Aysegul A.Aldaz, MarceloDuctal Carcinoma in SituBreast CancerGene Expresssionhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ductal 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 ERBB2þ) displayed signatures characteristic of activated Treg cells (CD4þ/CD25þ/FOXP3þ) and CTLA4þ/CD86þ 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.Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gong, Ting. University Of Texas; Estados UnidosFil: Lu, Yue. University Of Texas; Estados UnidosFil: Lee, Jaeho. University Of Texas; Estados UnidosFil: Zhong, Yi. University Of Texas; Estados UnidosFil: Lacunza, Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Butti, Matias. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Takata, Yoko. University Of Texas; Estados UnidosFil: Gaddis, Sally. University Of Texas; Estados UnidosFil: Shen, Jianjun. University Of Texas; Estados UnidosFil: Estecio, Marcos R.. University Of Texas; Estados UnidosFil: Sahin, Aysegul A.. University Of Texas; Estados UnidosFil: Aldaz, Marcelo. University Of Texas; Estados UnidosAmerican Association For Cancer Research2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/13711Abba, Martín Carlos; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; et al.; A molecular portrait of high-grade Ductal Carcinoma in situ; American Association For Cancer Research; Cancer Research; 75; 18; 9-2015; 1-110008-54721538-7445enginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-15-0506info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/75/18/3980info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:15:15Zoai:ri.conicet.gov.ar:11336/13711instacron: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:34982025-10-15 15:15:15.324CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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
Ductal Carcinoma in Situ
Breast Cancer
Gene Expresssion
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, Matias
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, Marcelo
author Abba, Martín Carlos
author_facet Abba, Martín Carlos
Gong, Ting
Lu, Yue
Lee, Jaeho
Zhong, Yi
Lacunza, Ezequiel
Butti, Matias
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, Marcelo
author_role author
author2 Gong, Ting
Lu, Yue
Lee, Jaeho
Zhong, Yi
Lacunza, Ezequiel
Butti, Matias
Takata, Yoko
Gaddis, Sally
Shen, Jianjun
Estecio, Marcos R.
Sahin, Aysegul A.
Aldaz, Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ductal Carcinoma in Situ
Breast Cancer
Gene Expresssion
topic Ductal Carcinoma in Situ
Breast Cancer
Gene Expresssion
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
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 ERBB2þ) displayed signatures characteristic of activated Treg cells (CD4þ/CD25þ/FOXP3þ) and CTLA4þ/CD86þ 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.
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gong, Ting. University Of Texas; Estados Unidos
Fil: Lu, Yue. University Of Texas; Estados Unidos
Fil: Lee, Jaeho. University Of Texas; Estados Unidos
Fil: Zhong, Yi. University Of Texas; Estados Unidos
Fil: Lacunza, Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Butti, Matias. Universidad Nacional de La Plata. Facultad de Ciencias Medicas. Centro de Investigaciones Inmunologicas Basicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Takata, Yoko. University Of Texas; Estados Unidos
Fil: Gaddis, Sally. University Of Texas; Estados Unidos
Fil: Shen, Jianjun. University Of Texas; Estados Unidos
Fil: Estecio, Marcos R.. University Of Texas; Estados Unidos
Fil: Sahin, Aysegul A.. University Of Texas; Estados Unidos
Fil: Aldaz, Marcelo. University Of Texas; Estados Unidos
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 ERBB2þ) displayed signatures characteristic of activated Treg cells (CD4þ/CD25þ/FOXP3þ) and CTLA4þ/CD86þ 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/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/11336/13711
Abba, Martín Carlos; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; et al.; A molecular portrait of high-grade Ductal Carcinoma in situ; American Association For Cancer Research; Cancer Research; 75; 18; 9-2015; 1-11
0008-5472
1538-7445
url http://hdl.handle.net/11336/13711
identifier_str_mv Abba, Martín Carlos; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; et al.; A molecular portrait of high-grade Ductal Carcinoma in situ; American Association For Cancer Research; Cancer Research; 75; 18; 9-2015; 1-11
0008-5472
1538-7445
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
info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/75/18/3980
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 13.22299

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