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Genomic Organization of Amplified MYC Genes Suggests Distinct Mechanisms of Amplification in Tumorigenesis

¹ Unité Stabilité des Génomes, Département de Structure et Dynamique des Génomes, ² Unite d'Expression Génétiques et Maladies, Département de Biologie du Développement, and ³ Unité des Papillomavirus, Département de Virologie, Institut Pasteur; and Service de ⁴ Génétique Oncologique and ⁵ Pathologie, Section Médicale, Institut Curie, Paris, France

Requests for reprints: Aaron Bensimon and Chiara Conti, Unité Stabilité Jes Génomes, Structure et Dynamique des Génomes, Pasteur Institute, 25, rue Dr. Roux, Paris cedex, France 75724. Phone: 33-140613240; Fax: 33-145688790; E-mail: abensim{at}pasteur.fr and cconti{at}pasteur.fr.

Integration of the human papillomavirus (HPV) genome into the host genome is associated with the disruption of the HPV E2 gene and with amplification and rearrangement of the viral and flanking cellular sequences. Molecular characterization of the genomic structures of coamplified HPV sequences and oncogenes provides essential information concerning the mechanisms of amplification and their roles in carcinogenesis. Using fluorescent hybridization on stretched DNA molecules in two cervical cancer–derived cell lines, we have elucidated the genomic structures of amplified regions containing HPV/myc genes over several hundreds of kilobases. Direct visualization of hybridization signals on individual DNA molecules suggests that overreplication and breakage-fusion-bridge–type mechanisms are involved in the genomic instability associated with HPV cervical cancers. Further analysis from two other genital cancer–derived cell lines reveals a recurrent motif of amplification, probably generated by a common mechanism involving overreplication upon viral integration. Interestingly, different amplification patterns seem to be correlated with the disease outcome, thus providing new insights into HPV-related cancer development and tumor progression.

Key Words: Genomic instability • amplification profile • HPV/myc amplicon • Single molecule approach

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