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Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis

journal contribution
submitted on 2024-09-24, 09:22 and posted on 2024-09-24, 09:23 authored by Wouter Hendrickx, Ines Simeone, Samreen Anjum, Younes Mokrab, François Bertucci, Pascal Finetti, Giuseppe Curigliano, Barbara Seliger, Luigi Cerulo, Sara Tomei, Lucia Gemma Delogu, Cristina Maccalli, Ena Wang, Lance D. Miller, Francesco M. Marincola, Michele Ceccarelli, Davide Bedognetti

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.

Other Information

Published in: OncoImmunology
License: https://creativecommons.org/licenses/by-nc/3.0/  
See article on publisher's website: https://dx.doi.org/10.1080/2162402x.2016.1253654

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

Taylor & Francis

Publication Year

  • 2017

License statement

This Item is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported International License.

Institution affiliated with

  • Sidra Medical and Research Center (2015-2017)
  • Hamad Bin Khalifa University
  • Qatar Computing Research Institute - HBKU