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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/13711
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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 Técnicas2025-09-29T10:18:02Zoai: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:34982025-09-29 10:18:03.253CONICET 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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13.070432 |