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01.06.2012 | Original Article

Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape

verfasst von: Mónica Bernal, Fernando García-Alcalde, Angel Concha, Carlos Cano, Armando Blanco, Federico Garrido, Francisco Ruiz-Cabello

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 6/2012

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Abstract

Aim

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).

Findings

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.

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Titel: Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape
verfasst von: Mónica Bernal
Fernando García-Alcalde
Angel Concha
Carlos Cano
Armando Blanco
Federico Garrido
Francisco Ruiz-Cabello
Publikationsdatum: 01.06.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 6/2012
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1147-7

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Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape

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