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Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma

Oncogene volume 24, pages 7094–7104 (2005)Cite this article

Abstract

Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a ‘cervical cancer proliferation cluster’ composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P=0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.

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Acknowledgements

The work at the Institut Curie was supported by the ‘Programme Génomique du Ministère chargé de la Recherche’ for the Affymetrix experiments, La Ligue Contre le Cancer and the Association pour la Recherche contre le Cancer. The work at the Weizmann Institute was supported in part by a grant from the Ridgefield Foundation. The work of ED at the Institut Curie was supported by a Rotschild-Mayent Fellowship. We thank Rachida Bouarich and Jérôme Bourdin for excellent technical assistance.

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Author notes

  1. Michal Sheffer and Dafna Tsafrir: These authors contributed equally to the analysis of the data

Authors and Affiliations

  1. Département de Biologie des Tumeurs, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Christophe Rosty, Martine Peter, Patricia de Crémoux, Jérôme Couturier & Xavier Sastre-Garau

  2. Oncologie Moléculaire UMR144 CNRS, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Christophe Rosty, Nicolas Stransky & François Radvanyi

  3. Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel

    Michal Sheffer, Dafna Tsafrir, Ilan Tsafrir & Eytan Domany

  4. Département de Radiothérapie, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Anne de La Rochefordière

  5. Département de Chirurgie, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Rémy Salmon

  6. Département d'Oncologie Médicale, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Thierry Dorval

  7. Département de Transfert, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Jean Paul Thiery

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  1. Christophe Rosty
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Correspondence to Xavier Sastre-Garau.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Rosty, C., Sheffer, M., Tsafrir, D. et al. Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma. Oncogene 24, 7094–7104 (2005). https://doi.org/10.1038/sj.onc.1208854

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