Your browser doesn't support javascript.
loading
Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis.
Hendrickx, Wouter; Simeone, Ines; Anjum, Samreen; Mokrab, Younes; Bertucci, François; Finetti, Pascal; Curigliano, Giuseppe; Seliger, Barbara; Cerulo, Luigi; Tomei, Sara; Delogu, Lucia Gemma; Maccalli, Cristina; Wang, Ena; Miller, Lance D; Marincola, Francesco M; Ceccarelli, Michele; Bedognetti, Davide.
Afiliação
  • Hendrickx W; Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Simeone I; Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar; Department of Science and Technology, University of Sannio, Benevento, Italy.
  • Anjum S; Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar.
  • Mokrab Y; Division of Biomedical Informatics, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Bertucci F; Département d'Oncologie Moléculaire, Center de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France; Département d'Oncologie Médicale, CRCM, Institut Paoli-Calmettes, Marseille, France; Faculté de Médecine, Aix-Marseille Université,
  • Finetti P; Département d'Oncologie Moléculaire, Center de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes , INSERM UMR1068, CNRS UMR725 , Marseille, France.
  • Curigliano G; Division of Experimental Therapeutics, Division of Medical Oncology, European Institute of Oncology , Milan, Italy.
  • Seliger B; Institute of Medical Immunology, Martin Luther University Halle-Wittenberg , Halle, Germany.
  • Cerulo L; Department of Science and Technology, University of Sannio, Benevento, Italy; BIOGEM Research Center, Ariano Irpino, Italy.
  • Tomei S; Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Delogu LG; Department of Chemistry and Pharmacy, University of Sassari , Sassari, Italy.
  • Maccalli C; Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Wang E; Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Miller LD; Department of Cancer Biology, Wake Forest School of Medicine , Winston-Salem, NC, USA.
  • Marincola FM; Office of the Chief Research Officer (CRO), Research Branch, Sidra Medical and Research Center , Doha, Qatar.
  • Ceccarelli M; Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar.
  • Bedognetti D; Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
Oncoimmunology ; 6(2): e1253654, 2017.
Article em En | MEDLINE | ID: mdl-28344865
ABSTRACT
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.
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Oncoimmunology Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Qatar

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Oncoimmunology Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Qatar