1. Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression
- Author
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Mota, Alba, Oltra, Sara S., Selenica, Pier, Moiola, Cristian Pablo, Casas-Arozamena, Carlos, López-Gil, Carlos, Diaz, Eva, Gatius, Sonia, Ruiz-Miro, María, Calvo, Ana, Rojo-Sebastián, Alejandro, Hurtado Blanco, P, Piñeiro, Health Research Institute of Santiago de Compostela, Colás Ortega, Eva, Gil-Moreno, Antonio, Reis-Filho, Jorge S., Muinelo-Romay, Laura, Abal Posada, Miguel, Matias-Guiu, Xavier, Weigelt, Britta, Moreno-Bueno, Gema, Universitatt Autònoma de Barcelona, Institut Català de la Salut, [Mota A] MD Anderson International Foundation, Madrid, Spain. Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, Madrid, Spain. [Oltra SS] MD Anderson International Foundation, Madrid, Spain. Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, Madrid, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Selenica P] Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. [Moiola CP, Colas E] Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. Grup de Recerca Biomèdica en Ginecologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Casas-Arozamena C] Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain. [López-Gil C] Grup de Recerca Biomèdica en Ginecologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Rojo-Sebastián A] Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. Grup de Recerca Biomèdica en Ginecologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. MD Anderson Cancer Center, Madrid, Spain. [Gil-Moreno A] Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. Grup de Recerca Biomèdica en Ginecologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Ginecologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Instituto de Salud Carlos III, Xarxa de Bancs de Tumors de Catalunya, Red Nacional de Biobancos (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red Cáncer (España), Asociación Española Contra el Cáncer, Breast Cancer Research Foundation, and National Institutes of Health (US)
- Subjects
Gynaecological cancer ,Cancer Research ,Comparative Genomic Hybridization ,DNA Copy Number Variations ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Female::Uterine Neoplasms::Endometrial Neoplasms [DISEASES] ,Endometrial Neoplasms ,fenómenos genéticos::variación genética::heterogeneidad genética [FENÓMENOS Y PROCESOS] ,Clonal Evolution ,Genetic Heterogeneity ,Genetic ,Mutation ,Genetics ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Cancer genomics ,Humans ,Female ,Genetic Phenomena::Genetic Variation::Genetic Heterogeneity [PHENOMENA AND PROCESSES] ,neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales femeninos::neoplasias uterinas::neoplasias endometriales [ENFERMEDADES] ,Molecular Biology ,Phylogeny ,Endometri - Càncer - Aspectes genètics - Abstract
Analyzing different tumor regions by next generation sequencing allows the assessment of intratumor genetic heterogeneity (ITGH), a phenomenon that has been studied widely in some tumor types but has been less well explored in endometrial carcinoma (EC). In this study, we sought to characterize the spatial and temporal heterogeneity of 9 different ECs using whole-exome sequencing, and by performing targeted sequencing validation of the 42 primary tumor regions and 30 metastatic samples analyzed. In addition, copy number alterations of serous carcinomas were assessed by comparative genomic hybridization arrays. From the somatic mutations, identified by whole-exome sequencing, 532 were validated by targeted sequencing. Based on these data, the phylogenetic tree reconstructed for each case allowed us to establish the tumors’ evolution and correlate this to tumor progression, prognosis, and the presence of recurrent disease. Moreover, we studied the genetic landscape of an ambiguous EC and the molecular profile obtained was used to guide the selection of a potential personalized therapy for this patient, which was subsequently validated by preclinical testing in patient-derived xenograft models. Overall, our study reveals the impact of analyzing different tumor regions to decipher the ITGH in ECs, which could help make the best treatment decision., Tissue samples were obtained with the support of the MD Anderson Foundation Biobank (record number B.0000745, ISCIII National Biobank Record), the “Xarxa Catalana de Bancs de Tumors” and “Plataforma de Biobancos” ISCIII (PT13/0010/0014, B.000609). This study has been supported by the Spanish Ministry of Economy and Innovation (PID2019-104644RB-I00 (GMB), the Instituto de Salud Carlos III (ISCIII, CIBERONC, CB16/12/00295 - GMB-, CB16/12/00328 -EC, AGM- and CB16/12/00231 -XMG- [all partly supported by FEDER funds]) and by the AECC Scientific Foundation (FC_AECC PROYE19036MOR -GMB- and Coordinated groups 2018 -XMG, AGM, GMB-). SO is funded by an AECC-postdoctoral grant (2020). JSR-F and BW are funded in part by the Breast Cancer Research Foundation and in part by the NIH/NCI P50 CA247749 01 grant. Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748; MSK).
- Published
- 2022