Canto Luisa Matos, da Silva Jenilson Mota, Castelo-Branco Patrícia Valèria, da Silva Ingrid Monteiro, Nogueira Leudivan, Fonseca-Alves Carlos Eduardo, Khayat André, Birbrair Alexander, Pereira Silma Regina
Clinical Genetics Department, University Hospital of Southern Denmark, 7100 Vejle, Denmark.
Postgraduate Program in Health Science, Federal University of Maranhão, São Luís 65080-805, MA, Brazil.
Cancers (Basel). 2022 Jul 20;14(14):3514. doi: 10.3390/cancers14143514.
High-throughput DNA sequencing has allowed for the identification of genomic alterations and their impact on tumor development, progression, and therapeutic responses. In PSCC, for which the incidence has progressively increased worldwide, there are still limited data on the molecular mechanisms involved in the disease pathogenesis. In this study, we characterized the mutational signature of 30 human papillomavirus (HPV)-associated PSCC cases from Latin Americans, using whole-exome sequencing. Copy number variations (CNVs) were also identified and compared to previous array-generated data. Enrichment analyses were performed to reveal disrupted pathways and to identify alterations mapped to HPV integration sites (HPVis) and miRNA-mRNA hybridization regions. Among the most frequently mutated genes were , , , , , , , , , , and . Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (, , , , , , , , , and ), thus increasing our understanding of the potential HPV-disrupted pathways. Therefore, our study reveals innovative targets with potential therapeutic benefits for HPV-associated PSCCs. The CNV analysis by sequencing (CNV-seq) revealed five cancer-associated genes as the most frequent with gains (, , , , and ), while 30% of the tumors showed with loss. Additionally, four cancer-associated genes (, , , and ) carried untranslated regions (UTRs) variants, which may impact gene regulation by affecting the miRNAs hybridization regions. Altogether, these data contribute to the characterization of the mutational spectrum and its impact on cellular signaling pathways in PSCC, thus reinforcing the pivotal role of HPV infection in the molecular pathogenesis of these tumors.
高通量DNA测序有助于识别基因组改变及其对肿瘤发生、发展和治疗反应的影响。在世界范围内发病率逐渐上升的口腔鳞状细胞癌（PSCC）中，关于该疾病发病机制所涉及的分子机制的数据仍然有限。在本研究中，我们使用全外显子测序对30例来自拉丁美洲人的人乳头瘤病毒（HPV）相关PSCC病例的突变特征进行了表征。还鉴定了拷贝数变异（CNV）并与先前通过阵列生成的数据进行了比较。进行了富集分析以揭示被破坏的通路，并识别映射到HPV整合位点（HPVis）和miRNA-mRNA杂交区域的改变。最常发生突变的基因包括 、 、 、 、 、 、 、 、 、 以及 。值得注意的是，这些改变的基因中有92%位于HPVis处。我们还在10个新基因（ 、 、 、 、 、 、 、 、 以及 ）中发现了突变，从而加深了我们对潜在的HPV破坏通路的理解。因此，我们的研究揭示了对HPV相关PSCC具有潜在治疗益处的创新靶点。通过测序进行的CNV分析（CNV-seq）显示，五个癌症相关基因是最常见的获得性基因（ 、 、 、 以及 ），而30%的肿瘤显示 缺失。此外，四个癌症相关基因（ 、 、 以及 ）携带非翻译区（UTR）变体，这可能通过影响miRNA杂交区域来影响基因调控。总之，这些数据有助于表征PSCC中的突变谱及其对细胞信号通路的影响，从而加强了HPV感染在这些肿瘤分子发病机制中的关键作用。
