Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications

Breast Cancer Research

Hubert Hondermarck¹  Véronique Verrièle²  Olivier Kerdraon²  Hamza Lasla³  Andrea Gombos⁴  Suzette Delaloge⁵  Delphine Loussouarn⁶  Mario Campone⁷  Wilfried Gouraud⁸  Catherine Guérin-Charbonnel⁸  Pascal Jézéquel⁹  Jérôme Lemonnier^1,10  Florence Dalenc^1,11  Jean-Luc Canon^1,12 

[1]0000 0000 8831 109X, grid.266842.c, School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, 2308, Callaghan, NSW, Australia

[2]0000 0000 9437 3027, grid.418191.4, Laboratoire d’Anatomie et Cytologie Pathologiques, Institut de Cancérologie de l’Ouest, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[3]0000 0000 9437 3027, grid.418191.4, Unité de Bioinfomique, Institut de Cancérologie de l’Ouest, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[4]0000 0001 0684 291X, grid.418119.4, Oncologie Médicale, Institut Jules Bordet, 121 Bd de Waterloo, 1000, Bruxelles, Belgium

[5]0000 0001 2284 9388, grid.14925.3b, Oncologie Médicale, Gustave Roussy, 114 rue Edouard Vaillant, 94800, Villejuif, France

[6]0000 0004 0472 0371, grid.277151.7, Départment d’Anatomie et Cytologie Pathologiques, Centre Hospitalo-Universitaire, 1 place Alexis Ricordeau, 44093, Nantes, France

[7]CRCINA, UMR 1232 INSERM, Université de Nantes, Université d’Angers, Institut de Recherche en Santé-Université de Nantes, BP 70721, 8 Quai Moncousu, 44007, Nantes Cedex 1, France

[8]0000 0000 9437 3027, grid.418191.4, Oncologie Médicale, Institut de Cancérologie de l’Ouest, René Gauducheau, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[9]Département de Biopathologie, Unité Mixte de Génomique du Cancer, Institut de Cancérologie de l’Ouest – site René Gauducheau, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[10]0000 0000 9437 3027, grid.418191.4, Unité de Bioinfomique, Institut de Cancérologie de l’Ouest, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[11]CRCINA, INSERM, CNRS, Université de Nantes, Université d’Angers, Institut de Recherche en Santé-Université de Nantes, BP 70721, 8 Quai Moncousu, 44007, Nantes Cedex 1, France

[12]Département de Biopathologie, Unité Mixte de Génomique du Cancer, Institut de Cancérologie de l’Ouest – site René Gauducheau, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[13]0000 0000 9437 3027, grid.418191.4, Unité de Bioinfomique, Institut de Cancérologie de l’Ouest, Bd Jacques Monod, 44805, Saint Herblain Cedex, France

[14]CRCINA, UMR 1232 INSERM, Université de Nantes, Université d’Angers, Institut de Recherche en Santé-Université de Nantes, BP 70721, 8 Quai Moncousu, 44007, Nantes Cedex 1, France

[15]UCBG, R&D UNICANCER, Fédération Nationale des Centres de Lutte Contre le Cancer, 101 rue de Tolbiac, 75013, Paris Cedex 13, France

[16]grid.488470.7, Oncologie Médicale, IUCT-Oncopole, 1 Av Irène Joliot-Curie, 31100, Toulouse, France

[17]grid.490655.b, Oncologie-Hématologie, Grand Hôpital de Charleroi, 3 Grand’Rue, 6000, Charleroi, Belgium

关键词: Breast cancer;    Triple-negative;    Transcriptomics;    Molecular subtypes;    Immunome;    Tertiary lymphoid structures;    Neurogenesis;   

DOI  :  10.1186/s13058-019-1148-6

来源: publisher

【 摘 要 】

BackgroundHeterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC), and therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study was to define robust TNBC subtypes with clinical relevance.MethodsGene expression profiling by means of DNA chips was conducted in an internal TNBC cohort composed of 238 patients. In addition, external data (n = 257), obtained by using the same DNA chip, were used for validation. Fuzzy clustering was followed by functional annotation of the clusters. Immunohistochemistry was used to confirm transcriptomics results: CD138 and CD20 were used to test for plasma cell and B lymphocyte infiltrations, respectively; MECA79 and CD31 for tertiary lymphoid structures; and UCHL1/PGP9.5 and S100 for neurogenesis.ResultsWe identified three molecular clusters within TNBC: one molecular apocrine (C1) and two basal-like-enriched (C2 and C3). C2 presented pro-tumorigenic immune response (immune suppressive), high neurogenesis (nerve infiltration), and high biological aggressiveness. In contrast, C3 exhibited adaptive immune response associated with complete B cell differentiation that occurs in tertiary lymphoid structures, and immune checkpoint upregulation. External cohort subtyping by means of the same approach proved the robustness of these results. Furthermore, plasma cell and B lymphocyte infiltrates, tertiary lymphoid structures, and neurogenesis were validated at the protein levels by means of histological evaluation and immunohistochemistry.ConclusionOur work showed that TNBC can be subcategorized in three different subtypes characterized by marked biological features, some of which could be targeted by specific therapies.

【 授权许可】

CC BY