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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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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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Abbreviations

APM:

Antigen processing machinery

CRC:

Colorectal cancer

HLA:

Human leucocyte antigen

MHC:

Major histocompatibility complex

MMR:

Mismatch repair

MSI:

Microsatellite instability

MSS:

Microsatellite stability

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Acknowledgments

The authors thank Eva García, Antonia Moreno and Ana Isabel Rodríguez for technical assistance. They are also grateful to the Tumour-Tissue Biobank of Virgen de las Nieves University Hospital for providing study samples. This investigation was partially supported by grants from the Fondo de Investigaciones Sanitarias (08/0528), Red Genómica del Cáncer (RETICRD 06/020), Consejería de Salud de la Junta de Andalucía (PI-0080-2010), Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía (P08-TIC-4299), Dirección General de Investigación y Gestión del Plan Nacional I + D+i (TIN2009-13489), Proyecto de Investigación de Excelencia (CTS-3952, CVI-4740 and P06/-CTS-02200) and Plan Andaluz de Investigación (PAI, Group CTS) and from the European Searchable Tumour Cell Line Database (ESTDAB) project, contract No. QLRI-CT-2001-01325 (http://www.ebi.ac.uk/estdab), the European Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumour immunology (ENACT) project (European community LSHC-CT-2004-503306) and the Cancer Immunotherapy project (European community OJ 2004/c158,18234).

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Clinical Analysis and Immunology, Virgen de las Nieves University Hospital, Granada, Spain

    Mónica Bernal, Federico Garrido & Francisco Ruiz-Cabello

  2. Department of Bioinformatics and Genomics, Príncipe Felipe Research Centre, Valencia, Spain

    Fernando García-Alcalde

  3. Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain

    Fernando García-Alcalde, Carlos Cano & Armando Blanco

  4. Department of Anatomical Pathology, Virgen de las Nieves University Hospital, Granada, Spain

    Angel Concha

  5. Department of Biochemistry, Molecular Biology III and Immunology, School of Medicine, University of Granada, Granada, Spain

    Federico Garrido & Francisco Ruiz-Cabello

  6. Avenida de las Fuerzas Armadas s/n, 18014, Granada, Spain

    Francisco Ruiz-Cabello

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  1. Mónica Bernal
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  2. Fernando García-Alcalde
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  3. Angel Concha
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  4. Carlos Cano
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  7. Francisco Ruiz-Cabello
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Correspondence to Francisco Ruiz-Cabello.

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Bernal, M., García-Alcalde, F., Concha, A. et al. Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape. Cancer Immunol Immunother 61, 803–816 (2012). https://doi.org/10.1007/s00262-011-1147-7

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  • DOI: https://doi.org/10.1007/s00262-011-1147-7

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