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  • Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

1 mai 2016Scientific Reports

DOI : 10.1038/srep18517

Auteurs

Magali Michaut, Suet-Feung Chin, Ian Majewski, Tesa M. Severson, Tycho Bismeijer, Leanne de Koning, Justine K. Peeters, Philip C. Schouten, Oscar M. Rueda, Astrid J. Bosma, Finbarr Tarrant, Yue Fan, Beilei He, Zheng Xue, Lorenza Mittempergher, Roelof J.C. Kluin, Jeroen Heijmans, Mireille Snel, Bernard Pereira, Andreas Schlicker, Elena Provenzano, Hamid Raza Ali, Alexander Gaber, Gillian O’Hurley, Sophie Lehn, Jettie J.F. Muris, Jelle Wesseling, Elaine Kay, Stephen John Sammut, Helen A. Bardwell, Aurélie S. Barbet, Floriane Bard, Caroline Lecerf, Darran P. O’Connor, Daniël J. Vis, Cyril H. Benes, Ultan McDermott, Mathew J. Garnett, Iris M. Simon, Karin Jirström, Thierry Dubois, Sabine C. Linn, William M. Gallagher, Lodewyk F.A. Wessels, Carlos Caldas, Rene Bernards

Résumé

Abstract

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT) and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

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