BACKGROUND: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. MATERIAL AND METHODS: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. RESULTS: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. CONCLUSIONS: MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
BACKGROUND: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and humanepidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. MATERIAL AND METHODS: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. RESULTS: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. CONCLUSIONS: MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
Authors: Nicole Sänger; Eugen Ruckhäberle; Giampaolo Bianchini; Tomas Heinrich; Karin Milde-Langosch; Volkmar Müller; Achim Rody; Erich Franz Solomayer; Tanja Fehm; Uwe Holtrich; Sven Becker; Thomas Karn Journal: Mol Oncol Date: 2014-04-15 Impact factor: 6.603
Authors: Ana M Gonzalez-Angulo; Takayuki Iwamoto; Shuying Liu; Huiqin Chen; Kim-Anh Do; Gabriel N Hortobagyi; Gordon B Mills; Funda Meric-Bernstam; W Fraser Symmans; Lajos Pusztai Journal: Clin Cancer Res Date: 2012-01-10 Impact factor: 12.531
Authors: Richard A Morgan; Nachimuthu Chinnasamy; Daniel Abate-Daga; Alena Gros; Paul F Robbins; Zhili Zheng; Mark E Dudley; Steven A Feldman; James C Yang; Richard M Sherry; Giao Q Phan; Marybeth S Hughes; Udai S Kammula; Akemi D Miller; Crystal J Hessman; Ashley A Stewart; Nicholas P Restifo; Martha M Quezado; Meghna Alimchandani; Avi Z Rosenberg; Avindra Nath; Tongguang Wang; Bibiana Bielekova; Simone C Wuest; Nirmala Akula; Francis J McMahon; Susanne Wilde; Barbara Mosetter; Dolores J Schendel; Carolyn M Laurencot; Steven A Rosenberg Journal: J Immunother Date: 2013-02 Impact factor: 4.456
Authors: Teresa Cabezón; Irina Gromova; Pavel Gromov; Reza Serizawa; Vera Timmermans Wielenga; Niels Kroman; Julio E Celis; José M A Moreira Journal: Mol Cell Proteomics Date: 2012-11-20 Impact factor: 5.911