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 × 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.
在HPV相关癌变中，已有研究报道了部分因病毒插入而发生改变且可能成为治疗靶点的癌症相关基因，但迄今为止尚未对这些事件（包括低复现性靶点）进行定量评估。为系统记录这些现象，我们构建并分析了包含1455例病例的数据库，涵盖HPV基因型和肿瘤定位信息。根据病毒整合靶向的人类DNA序列，将其分为"非复现性"（仅单例报道；838个位点）、"弱复现性"（两例报道；82个位点）和"高复现性"（≥3例；43个位点）。Gencode数据库中癌症相关靶基因总体占比为3.3%，而在病毒整合靶向基因中，该比例在"非复现性"基因中升至6.5%，"弱复现性"基因中达11.4%，"高复现性"基因中高达40.1%（p=4.9×10−4）。高危型HPV16/18/45相关肿瘤中的该比例也显著高于其他基因型。在HPV插入靶向的基因中，30.2%对应直接或间接的药物靶点，其中"高复现性"靶点中该比例升至50%。通过文献数据和DepMap 23Q4数据库分析，我们发现病毒插入靶向基因可能成为参与HPV相关致癌过程的新候选基因。对HPV相关癌症中病毒/宿主融合DNA序列进行更系统化的表征，将有助于深化对HPV驱动癌变机制的认识，并推动个体化治疗方案的发展。
HPV DNA Integration at Actionable Cancer-Related Genes Loci in HPV-Associated Carcinomas
肿瘤(癌症)患者之家