Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in node-negative breast cancer.
The majority of gene expression signatures developed to predict the likelihood to relapse in breast cancer (BC) patients assigns a high risk score to patients with Estrogen Receptor (ER) negative or highly proliferating tumors. We aimed to identify a signature of differentially expressed (DE) metagenes, rather than single DE genes, associated with distant metastases beyond classical risk factors. We used 105 gene expression profiles from consecutive BCs to identify metagenes whose prognostic role was defined on an independent series of 92 ESR1+/ERBB2- node-negative BCs (42 cases developing metastases within 5 years from diagnosis and 50 cases metastasis-free for more than 5 years, comparable for age, tumor size, ER status and surgery). Findings were validated on publicly available datasets of 684 node-negative BCs including all the subtypes. Only a metagene containing interferon-induced genes (IFN metagene) proved to be predictive of distant metastasis in our series of patients with ESR1+/ERBB2- tumors (P = 0.029), and such a finding was validated on 457 ESR1+/ERBB2- BCs from public datasets (P = 0.0424). Conversely, the IFN metagene was associated with a low risk of metastasis in 104 ERBB2+ tumors (P = 0.0099) whereas it did not prove to significantly affect prognosis in 123 ESR1-/ERBB2- tumors (P = 0.2235). A complex prognostic interaction was revealed in ESR1+/ERBB2- and ERBB2+ tumors when the association between the IFN metagene and a T-cell metagene was considered. The study confirms the importance of analyzing prognostic variables separately within BC subtypes, highlights the advantages of using metagenes rather than genes, and finally identifies in node-negative ESR1+/ERBB2- BCs, the unfavorable role of high IFN metagene expression.
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Maurizio
M
Callari
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Valeria
V
Musella
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Eleonora
E
Di Buduo
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Marialuisa
M
Sensi
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Patrizia
P
Miodini
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Matteo
M
Dugo
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy.
Rosaria
R
Orlandi
Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy.
Roberto
R
Agresti
Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy.
Biagio
B
Paolini
Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy.
Maria Luisa
ML
Carcangiu
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy. Electronic address: vera.cappelletti@istitutotumori.mi.it.
Vera
V
Cappelletti
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milan, Italy. Electronic address: mariagrazia.daidone@istitutotumori.mi.it.
Maria Grazia
MG
Daidone
D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction
D007372:Interferons
Breast cancer; Breast cancer subtypes; Distant metastasis; Gene expression profiles; IFN-metagene