title: Melanoma antigen family A identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation.
abstract: 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.
  
  
  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: Department of Obstetrics and Gynecology, JW Goethe-University, Frankfurt, Germany. t.karn@em.uni-frankfurt.de
authors: Thomas
authors: T
authors: Karn
authors: Lajos
authors: L
authors: Pusztai
authors: Eugen
authors: E
authors: Ruckhäberle
authors: Cornelia
authors: C
authors: Liedtke
authors: Volkmar
authors: V
authors: Müller
authors: Marcus
authors: M
authors: Schmidt
authors: Dirk
authors: D
authors: Metzler
authors: Jing
authors: J
authors: Wang
authors: Kevin R
authors: KR
authors: Coombes
authors: Regine
authors: R
authors: Gätje
authors: Lars
authors: L
authors: Hanker
authors: Christine
authors: C
authors: Solbach
authors: Andre
authors: A
authors: Ahr
authors: Uwe
authors: U
authors: Holtrich
authors: Achim
authors: A
authors: Rody
authors: Manfred
authors: M
authors: Kaufmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001943:Breast Neoplasms / Q000145:classification* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002277:Carcinoma / Q000145:classification* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006305:Health Status Indicators; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058950:Melanoma-Specific Antigens / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D046228:Microarray Analysis; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D058950:Melanoma-Specific Antigens; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C072011:MAGEA1 protein, human; C508053:ERBB2 protein, human