title: Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
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.
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Magali
authors.initials: M
authors.lastname: Michaut
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ian
authors.initials: I
authors.lastname: Majewski
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Tesa M
authors.initials: TM
authors.lastname: Severson
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Tycho
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authors.lastname: Bismeijer
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.affiliation: Agendia NV, Science Park 406, 1098 XH Amsterdam, The Netherlands.
authors.forename: Justine K
authors.initials: JK
authors.lastname: Peeters
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Astrid J
authors.initials: AJ
authors.lastname: Bosma
authors.affiliation: Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.|OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin 4, Ireland.
authors.forename: Finbarr
authors.initials: F
authors.lastname: Tarrant
authors.affiliation: Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Beilei
authors.initials: B
authors.lastname: He
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xue
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Mittempergher
authors.affiliation: Genomic Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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authors.initials: RJ
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authors.affiliation: Agendia NV, Science Park 406, 1098 XH Amsterdam, The Netherlands.
authors.forename: Jeroen
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authors.lastname: Heijmans
authors.affiliation: Agendia NV, Science Park 406, 1098 XH Amsterdam, The Netherlands.
authors.forename: Mireille
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authors.lastname: Snel
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pereira
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Cambridge Experimental Cancer Medicine Centre (ECMR) and NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.|Cambridge Breast Unit and Cambridge University Hospitals, NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.|Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
authors.forename: Hamid Raza
authors.initials: HR
authors.lastname: Ali
authors.affiliation: Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, SE-221 85 Lund, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaber
authors.affiliation: OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin 4, Ireland.
authors.forename: Gillian
authors.initials: G
authors.lastname: O'Hurley
authors.affiliation: Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, SE-221 85 Lund, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lehn
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jettie J F
authors.initials: JJ
authors.lastname: Muris
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, RCSI ERC, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kay
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Stephen John
authors.initials: SJ
authors.lastname: Sammut
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Bardwell
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Aurélie S
authors.initials: AS
authors.lastname: Barbet
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Bard
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lecerf
authors.affiliation: Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Darran P
authors.initials: DP
authors.lastname: O'Connor
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Daniël J
authors.initials: DJ
authors.lastname: Vis
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Cyril H
authors.initials: CH
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authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Ultan
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authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
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authors.initials: MJ
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authors.affiliation: Agendia NV, Science Park 406, 1098 XH Amsterdam, The Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, SE-221 85 Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Translational Research Department, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.|OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin 4, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Department of EEMCS, Delft University of Technology, Delft, The Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.|Cambridge Experimental Cancer Medicine Centre (ECMR) and NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.|Cambridge Breast Unit and Cambridge University Hospitals, NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.|Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Agendia NV, Science Park 406, 1098 XH Amsterdam, The Netherlands.|Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D059645:Mutation Rate; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D020543:Proteome; D040901:Proteomics; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; D020543:Proteome; D014157:Transcription Factors