Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis
| العنوان: | Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis |
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| المؤلفون: | Francesco M. Marincola, Wouter Hendrickx, Cristina Maccalli, Barbara Seliger, Pascal Finetti, Giuseppe Curigliano, Lance D. Miller, Ines Simeone, Younes Mokrab, François Bertucci, Michele Ceccarelli, Davide Bedognetti, Ena Wang, Luigi Cerulo, Samreen Anjum, Lucia Gemma Delogu, Sara Tomei |
| المساهمون: | Multidisciplinary Breast Centre, UZ Leuven, Sidra Medical and Research Center, Department of Science and Technology, University of Sannio, Qatar Computing Research Institute [Doha, Qatar] (QCRI), Eli Lilly and Company Limited [Windlesham], Service d'Oncologie Médicale, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Medical Oncology, European Institute of Oncology [Milan] (ESMO), Institute for Transfusion Medicine, University Hospital Essen, BIOGEM, University of Sassari, Department of Molecular Oncology, Foundation San Raffaele Scientific Institute, Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Sidra Tower, Universitair Ziekenhuis Leuven (UZ Leuven), Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Hendrickx, W., Simeone, I., Anjum, S., Mokrab, Y., Bertucci, F., Finetti, P., Curigliano, G., Seliger, B., Cerulo, L, Tomei, S., Delogu, L. G., Maccalli, C., Wang, E., Miller, L. D., Marincola, F. M., Ceccarelli, M., Bedognetti, D., MITOYAN, Louciné |
| المصدر: | OncoImmunology OncoImmunology, Taylor & Francis, 2017, 6 (2), ⟨10.1080/2162402X.2016.1253654⟩ OncoImmunology, 2017, 6 (2), ⟨10.1080/2162402X.2016.1253654⟩ OncoImmunology, Vol 6, Iss 2 (2017) Oncoimmunology |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, chemokines, chemical and pharmacologic phenomena, Biology, lcsh:RC254-282, triple negative, 03 medical and health sciences, 0302 clinical medicine, Immune system, Germline mutation, Breast cancer, breast cancer, pd-l1, medicine, Immunology and Allergy, Gene, immune checkpoint, Original Research, Genetics, immune signatures, prognostic signatures, predictive signatures, FOXP3, Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Phenotype, Immune checkpoint, immunologic constant of rejection, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, exome sequencing, MAPK mutations, PD-L1, 030220 oncology & carcinogenesis, lcsh:RC581-607, mapk mutations |
| الوصف: | International audience; Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2162-4011 2162-402X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13cc6d52735d7b6387a46f04ae6286bfTest http://hdl.handle.net/11567/996136Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....13cc6d52735d7b6387a46f04ae6286bf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21624011 2162402X |
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