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, 7 (6), e39632

Non-random Integration of the HPV Genome in Cervical Cancer

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Non-random Integration of the HPV Genome in Cervical Cancer

Martina Schmitz et al. PLoS One.

Abstract

HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs) are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240). We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular genes, by HPV integration remains an issue to be fully resolved.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Chromosomal hotspots for HPV integration.
Depicted are integration sites located within the cytogenetic bands 3q28 (A), 4q13.3 (B), 8q24.21 (C), 13q22.1 (D) and 17q21.2 (E). Light blue arrows: genes affected by HPV integration; red arrows: HPV fusion transcripts described in this work; grey arrows: HPV fusion transcripts described by Kraus et al. 2008; green arrows: fragile site; dark blue arrows: microRNAs.
Figure 2
Figure 2. Sequence homologies between the HPV16 genome and the two adjoining genes TP63 and LEPREL1.
Three homologous stretches of up to 50 nucleotides are shown. The number of exact nucleotide matches is given in brackets (see also Sequences S1). The DNA loop between the two homologies located on LEPREL1 comprises 102.689 nucleotides; the second loop 269.968 nucleotides. Grey dots refer to the approximate location of the corresponding viral-cellular fusion transcripts detected in tumors D3829, T2107 and T4335 (from left to right).

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