Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach

It is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. Thi...

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Autores: Carmen, Sofía del, Sayagués, José María, Bengoechea, Óscar, Anduaga, María Fernanda, Alcázar, José A., Gervas, Ruth, García, Jacinto, Orfao, Alberto, Muñoz-Bellvis, Luís, Sarasquete, María Eugenia, Abad, María del Mar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/245369
Acceso en línea:http://hdl.handle.net/10261/245369
Access Level:acceso abierto
Palabra clave:Colorectal cancer
Clonal evolution
Anti-EGFR
Mutational profiles
Tumor heterogeneity
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spelling Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approachCarmen, Sofía delSayagués, José MaríaBengoechea, ÓscarAnduaga, María FernandaAlcázar, José A.Gervas, RuthGarcía, JacintoOrfao, AlbertoMuñoz-Bellvis, LuísSarasquete, María EugeniaAbad, María del MarColorectal cancerClonal evolutionAnti-EGFRMutational profilesTumor heterogeneityIt is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. This could be because the treatment decision is determined by the mutational profile of the primary tumor, regardless of the presence of small tumor subclones harboring RAS mutations in lymph nodes or liver metastases. We analyzed the mutational profile of the KRAS, NRAS, BRAF and PI3KCA genes using low-density microarray technology in samples of 26 paired primary tumors, 16 lymph nodes and 34 liver metastases from 26 untreated mCRC patients (n=76 samples). The most frequent mutations found in primary tumors were KRAS (15%) and PI3KCA (15%), followed by NRAS (8%) and BRAF (4%). The distribution of the mutations in the 16 lymph node metastases analyzed was as follows: 4 (25%) in KRAS gene, 3 (19%) in NRAS gene and 1 mutation each in PI3KCA and BRAF genes (6%). As expected, the most prevalent mutation in liver metastasis was in the KRAS gene (35%), followed by PI3KCA (9%) and BRAF (6%). Of the 26 cases studied, 15 (58%) displayed an overall concordance in the mutation status detected in the lymph node metastases and liver metastases compared with primary tumor, suggesting no clonal evolution. In contrast, the mutation profiles differed in the primary tumor and lymph node/metastases samples of the remaining 11 patients (48%), suggesting a spatial and temporal clonal evolution. We confirm the presence of different mutational profiles among primary tumors, lymph node metastases and liver metastases. Our results suggest the need to perform mutational analysis in all available tumor samples of patients before deciding to commence anti-EGFR treatment.This work has been partially supported by grants from the Instituto de Salud Carlos III (ISCIII; Ministerio de Sanidad y Consumo, Madrid, Spain) (PI18/00282), the Gerencia Regional de Salud de Castilla y León, Valladolid, Spain (GRS1302/A/16), the RTICC of the ISCIII (RD12/0020/0035-FEDER, RD12/0036/0048-FEDER) and CIBERONC (CB16/12/00400 and CB16/12/00233), the Fundación Memoria de Don Samuel Solórzano Barruso (Salamanca, Spain) and the Fundación Eugenio Rodríguez Pascual, (Madrid, Spain). JM Sayagués and ME Sarasquete are supported by grants (CES11/004 and CP13/00080) from the ISCIII, Ministerio de Ciencia e Innovación, Madrid, Spain.Impact JournalsInstituto de Salud Carlos IIIMinisterio de Sanidad y Consumo (España)Junta de Castilla y LeónFundación Memoria de D. Samuel Solorzano BarrusoFundación Eugenio Rodríguez PascualMinisterio de Ciencia e Innovación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120182021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/245369reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.18632/oncotarget.26081Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2453692026-05-22T06:33:51Z
dc.title.none.fl_str_mv Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
title Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
spellingShingle Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
Carmen, Sofía del
Colorectal cancer
Clonal evolution
Anti-EGFR
Mutational profiles
Tumor heterogeneity
title_short Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
title_full Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
title_fullStr Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
title_full_unstemmed Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
title_sort Spatio-temporal tumor heterogeneity in metastatic CRC tumors: A mutational-based approach
dc.creator.none.fl_str_mv Carmen, Sofía del
Sayagués, José María
Bengoechea, Óscar
Anduaga, María Fernanda
Alcázar, José A.
Gervas, Ruth
García, Jacinto
Orfao, Alberto
Muñoz-Bellvis, Luís
Sarasquete, María Eugenia
Abad, María del Mar
author Carmen, Sofía del
author_facet Carmen, Sofía del
Sayagués, José María
Bengoechea, Óscar
Anduaga, María Fernanda
Alcázar, José A.
Gervas, Ruth
García, Jacinto
Orfao, Alberto
Muñoz-Bellvis, Luís
Sarasquete, María Eugenia
Abad, María del Mar
author_role author
author2 Sayagués, José María
Bengoechea, Óscar
Anduaga, María Fernanda
Alcázar, José A.
Gervas, Ruth
García, Jacinto
Orfao, Alberto
Muñoz-Bellvis, Luís
Sarasquete, María Eugenia
Abad, María del Mar
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Sanidad y Consumo (España)
Junta de Castilla y León
Fundación Memoria de D. Samuel Solorzano Barruso
Fundación Eugenio Rodríguez Pascual
Ministerio de Ciencia e Innovación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Colorectal cancer
Clonal evolution
Anti-EGFR
Mutational profiles
Tumor heterogeneity
topic Colorectal cancer
Clonal evolution
Anti-EGFR
Mutational profiles
Tumor heterogeneity
description It is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. This could be because the treatment decision is determined by the mutational profile of the primary tumor, regardless of the presence of small tumor subclones harboring RAS mutations in lymph nodes or liver metastases. We analyzed the mutational profile of the KRAS, NRAS, BRAF and PI3KCA genes using low-density microarray technology in samples of 26 paired primary tumors, 16 lymph nodes and 34 liver metastases from 26 untreated mCRC patients (n=76 samples). The most frequent mutations found in primary tumors were KRAS (15%) and PI3KCA (15%), followed by NRAS (8%) and BRAF (4%). The distribution of the mutations in the 16 lymph node metastases analyzed was as follows: 4 (25%) in KRAS gene, 3 (19%) in NRAS gene and 1 mutation each in PI3KCA and BRAF genes (6%). As expected, the most prevalent mutation in liver metastasis was in the KRAS gene (35%), followed by PI3KCA (9%) and BRAF (6%). Of the 26 cases studied, 15 (58%) displayed an overall concordance in the mutation status detected in the lymph node metastases and liver metastases compared with primary tumor, suggesting no clonal evolution. In contrast, the mutation profiles differed in the primary tumor and lymph node/metastases samples of the remaining 11 patients (48%), suggesting a spatial and temporal clonal evolution. We confirm the presence of different mutational profiles among primary tumors, lymph node metastases and liver metastases. Our results suggest the need to perform mutational analysis in all available tumor samples of patients before deciding to commence anti-EGFR treatment.
publishDate 2018
dc.date.none.fl_str_mv 2018
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/245369
url http://hdl.handle.net/10261/245369
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.18632/oncotarget.26081
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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