HPV DNA Integration at Actionable Cancer-Related Genes Loci in HPV-Associated Carcinomas

Simple Summary In many tumor types, the development of personalized treatments has been allowed by the optimal molecular characterization of tumor cell genome alterations. In most carcinomas associated with human papillomaviruses (HPV), the integration of part of the viral genome into the tumor cell genome may lead to alterations of cancer-related genes located at the integration locus. In order to assess the overall frequency of such an event, we analyzed a large series of cases for which HPV integration sites had been determined. We found that 40% of the genes located at highly (>= 3) recurrent HPV insertions corresponded to cancer-related genes. Moreover, about one-third of the genes targeted by HPV insertions correspond to actionable targets. These observations should lead to a more systematic analysis of HPV DNA integration patterns in HPV-associated carcinomas in order to identify highly specific tumor markers and develop personalized anti-tumor therapies.Abstract In HPV-associated carcinomas, some examples of cancer-related genes altered by viral insertion and corresponding to potential therapeutic targets have been described, but no quantitative assessment of these events, including poorly recurrent targets, has been reported to date. To document these occurrences, we built and analyzed a database comprised of 1455 cases, including HPV genotypes and tumor localizations. Host DNA sequences targeted by viral integration were classified as "non-recurrent" (one single reported case; 838 loci), "weakly recurrent" (two reported cases; 82 loci), and highly recurrent (>= 3 cases; 43 loci). Whereas the overall rate of cancer-related target genes was 3.3% in the Gencode database, this rate increased to 6.5% in "non-recurrent", 11.4% in "weakly recurrent", and 40.1% in "highly recurrent" genes targeted by integration (p = 4.9 x 10-4). This rate was also significantly higher in tumors associated with high-risk HPV16/18/45 than other genotypes. Among the genes targeted by HPV insertion, 30.2% corresponded to direct or indirect druggable targets, a rate rising to 50% in "highly recurrent" targets. Using data from the literature and the DepMap 23Q4 release database, we found that genes targeted by viral insertion could be new candidates potentially involved in HPV-associated oncogenesis. A more systematic characterization of HPV/host fusion DNA sequences in HPV-associated cancers should provide a better knowledge of HPV-driven carcinogenesis and favor the development of personalize patient treatments.