title: Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape.
abstract: OBJECTIVE
  We compared the expression of genes related to inflammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA- tumours and 6 MSS/HLA+ tumours (controls).
  
  
  RESULTS
  A first comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an Affymetrix(®) HG-U133-Plus-PM plate, identified 1974 differentially expressed genes (P < 0.05). We grouped genes in Gene Ontology functional categories: apoptotic programme (72 genes, P = 5.5·10(-3)), leucocyte activation (43 genes, P = 1.8·10(-5)), T-cell activation (24 genes, P = 6.3·10(-4)), inflammatory response (40 genes, 2.3·10(-2)) and cytokine production (10 genes, P = 1.9·10(-2)). Real-time PCR and immunohistochemical evaluation were used to validate the data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+T lymphocytes in the MSI group (P < 0.001). Finally, HLA-class I-negative tumours were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2,                            B2m) were downregulated in MSS/HLA-class I-negative CRCs (n = 6) in comparison to controls.
  
  
  CONCLUSIONS
  In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked differences in the composition and intensity of infiltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.
authors.affiliation: Department of Clinical Analysis and Immunology, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bernal
authors.forename: Fernando
authors.initials: F
authors.lastname: García-Alcalde
authors.forename: Angel
authors.initials: A
authors.lastname: Concha
authors.forename: Carlos
authors.initials: C
authors.lastname: Cano
authors.forename: Armando
authors.initials: A
authors.lastname: Blanco
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I
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