title: Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis.
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 asPDL1, PD1, FOXP3, IDO1, andCTLA4, 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 ofTP53were enriched in the immune favorable phenotype (ICR4). Conversely, the presence ofMAP3K1andMAP2K4mutations 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.
authors.affiliation: Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Wouter
authors.initials: W
authors.lastname: Hendrickx
authors.affiliation: Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar; Department of Science and Technology, University of Sannio, Benevento, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Simeone
authors.affiliation: Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar.
authors.forename: Samreen
authors.initials: S
authors.lastname: Anjum
authors.affiliation: Division of Biomedical Informatics, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Younes
authors.initials: Y
authors.lastname: Mokrab
authors.affiliation: 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, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Département d'Oncologie Moléculaire, Center de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes , INSERM UMR1068, CNRS UMR725 , Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Division of Experimental Therapeutics, Division of Medical Oncology, European Institute of Oncology , Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg , Halle, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.affiliation: Department of Science and Technology, University of Sannio, Benevento, Italy; BIOGEM Research Center, Ariano Irpino, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cerulo
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari , Sassari, Italy.
authors.forename: Lucia Gemma
authors.initials: LG
authors.lastname: Delogu
authors.affiliation: Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccalli
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine , Winston-Salem, NC, USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Office of the Chief Research Officer (CRO), Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Qatar Computing Research Institute, Hamad Bin Khalifa University , Doha, Qatar.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Tumor Biology, Immunology, and Therapy Section, Division of Translational Medicine, Research Branch, Sidra Medical and Research Center , Doha, Qatar.
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
keywords: Breast cancer; MAPK mutations; PD-L1; chemokines; exome sequencing; immune checkpoint; immune signatures; immunologic constant of rejection; predictive signatures; prognostic signatures; triple negative