title: Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis.
abstract: Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n= 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52],p= 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions.
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France; Department of Surgery; Institut Curie; Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Bonsang-Kitzis
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France; Laboratoire de Mathématiques et Modélisation d'Evry, Université d'Évry Val d'Essonne; UMR CNRS 8071, ENSIIE, USC INRA, France.
authors.forename: B
authors.initials: B
authors.lastname: Sadacca
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France.
authors.forename: A S
authors.initials: AS
authors.lastname: Hamy-Petit
authors.affiliation: Mines Paristech; PSL-Research University; CBIO-Centre for Computational Biology; Mines ParisTech; Fontainebleau, France; U900, INSERM; Institut Curie; Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Moarii
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Pinheiro
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Residual Tumor & Response to Treatment Laboratory; RT2Lab; Translational Research Department; Institut Curie; Paris, France; U932 Immunity and Cancer; INSERM; Institut Curie; Paris, France; Department of Surgery; Institut Curie; Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Reyal
keywords: immune signature; molecular subtypes; prognosis; triple-negative breast cancer