Expression of young HERV-H loci in the course of colorectal carcinoma and correlation with molecular subtypes
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Philippe Pérot1,7,*, Christina Susanne Mullins1,2,*, Magali Naville3, Cédric Bressan1, Maja Hühns4, Michael Gock5, Florian Kühn5, Jean-Nicolas Volff3, Véronique Trillet-Lenoir2, Michael Linnebacher6,*, François Mallet1,*
1Cancer Biomarkers Research Group, Joint Unit Hospices Civils de Lyon, bioMérieux, Centre Hospitalier Lyon Sud, Pierre Bénite, France
2Centre d’Investigation des Thérapeutiques en Oncologie et Hématologie, EMR 3738 Lyon Claude Bernard University, Institut de Cancérologie des Hospices Civils de Lyon, France
3Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS/Université Lyon I, Lyon, France
4Institute of Pathology, University Medicine Rostock, Rostock, Germany
5Department of General, Thoracic, Vascular and Transplantation Surgery, University Medicine Rostock, Rostock, Germany
6Department of General Surgery, Molecular Oncology and Immunotherapy, University Medicine Rostock, Rostock, Germany
7Current address: Institut Pasteur, Laboratory for Pathogen Discovery, Paris, France
*These authors have contributed equally to this work
Michael Linnebacher, e-mail: firstname.lastname@example.org
François Mallet, e-mail: email@example.com
Keywords: colorectal cancer, HERV-H, microsatellite instability, qRT-PCR, biomarker
Received: June 28, 2015 Accepted: October 13, 2015 Published: October 23, 2015
Background: Expression of the human endogenous retrovirus (HERV)-H family has been associated with colorectal carcinomas (CRC), yet no individual HERV-H locus expression has been thoroughly correlated with clinical data.
Here, we characterized HERV-H reactivations in clinical CRC samples by integrating expression profiles, molecular patterns and clinical data. Expression of relevant HERV-H sequences was analyzed by qRT-PCR on two well-defined clinical cohorts (n = 139 pairs of tumor and adjacent normal colon tissue) including samples from adenomas (n = 21) and liver metastases (n = 16). Correlations with clinical and molecular data were assessed.
Results: CRC specific HERV-H sequences were validated and found expressed throughout CRC disease progression. Correlations between HERV-H expression and lymph node invasion of tumor cells (p = 0.0006) as well as microsatellite instable tumors (p < 0.0001) were established. No association with regard to age, tumor localization, grading or common mutations became apparent. Interestingly, CRC expressed elements belonged to specific young HERV-H subfamilies and their 5′ LTR often presented active histone marks.
Conclusion: These results suggest a functional role of HERV-H sequences in colorectal carcinogenesis. The pronounced connection with microsatellite instability warrants a more detailed investigation. Thus, HERV-H sequences in addition to tumor specific mutations may represent clinically relevant, truly CRC specific markers for diagnostic, prognostic and therapeutic purposes.
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