Integrative analysis to identify genomic biomarkers in HPV positive oral cancer

综合分析鉴定 HPV 阳性口腔癌的基因组生物标志物

• 批准号: 10666904
• 负责人: MINGXIANG TENG
• 金额: $ 16.85万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666904
• 关键词: Accounting; Anatomy; Biological Markers; Cancer cell line; Cancerous; Candidate Disease Gene; Cell Line; Cells; ChIP-seq; Chromatin; Clinical; Collaborations; Collection; Data; Data Analyses; Data Science; Data Set; Discrimination; Dryness; Ensure; Epithelial Cells; Epithelium; Europe; Excision; Future; Genes; Genomics; Growth; Heterogeneity; High-Throughput Nucleotide Sequencing; Human Herpesvirus 4; Human Papillomavirus; Human papilloma virus infection; Infection; Knock-out; Knowledge; Malignant Neoplasms; Methods; Molecular; Multiomic Data; Mutation; Nasopharynx; Nature; Neoplasm Metastasis; North America; Oncogenes; Oncogenic; Oncogenic Viruses; Oral; Oropharyngeal; PIK3CG gene; Pathway interactions; Pattern; Predisposition; Proteins; Retinoblastoma Protein; Role; Sample Size; Signal Pathway; Signal Transduction; Site; TNF gene; TP53 gene; Testing; The Cancer Genome Atlas; Translating; Tumor Suppressor Proteins; Validation; Viral; Viral Load result; Virus; Virus Diseases; biomarker identification; cancer type; candidate marker; cellular transduction; data integration; data modeling; epigenomics; exome; experience; experimental study; fitness; genomic biomarker; genomic profiles; heterogenous data; improved; insight; knock-down; laboratory experiment; malignant mouth neoplasm; malignant oropharynx neoplasm; molecular dynamics; neoplastic cell; next generation sequencing; novel; novel therapeutics; oral biology; oral carcinogenesis; oral cavity epithelium; specific biomarkers; transcriptome; transcriptome sequencing; transcriptomics; trend; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Human papillomavirus positive (HPV+) oral cancer (OC), accounting for over 70% of oropharyngeal cancer cases in North America and Europe, was found to be more aggressive with a higher tendency of metastasis compared to HPV negative OC. It is believed that such aggressiveness is associated to the nature of its oncogenic mechanisms triggered by HPV infection. HPV encodes two potent oncogenes E6 and E7 that inactivate key tumor suppressors pRb and p53 and subsequently alter the expression spectrum of genes in oral epithelial cells. To identify the molecular mechanisms of HPV oncogenesis, numerous studies have compared the (epi)genomic profiles of HPV+ OC to normal oral epithelium, HPV negative OC, or other cancer types. These studies have generated high-throughput sequencing datasets using different methods (transcriptomic, genomic and epigenomic) and cellular conditions (normal, viral-infected and cancerous). However, these datasets were not fully explored due to lack of comparable analysis platform to efficiently interrogate them, especially when heterogeneity and batch effects are high across studies. We propose to leverage our data science experience as well as close wet-lab collaborations to perform integrative analysis to identify HPV-specific biomarkers in HPV+ OC. We propose to integrate (epi)genomic next generation sequencing datasets from 11 selected studies (with addition if more availability in the future), involving 3 data types, 13 cell lines, 3 viral infection stages and 2 anatomically similar sites. At the core of the analysis is to remove potential batch effects and biases of the integrated datasets and to set proper controls to nominate oncogenic biomarkers. To validate the findings, we propose both dry and wet-lab experiments to evaluate candidate biomarkers. Insights from the proposed study could advance our understanding of oral biology and potentially translate to novel therapeutics for HPV+ OC.

项目摘要/摘要 人乳头瘤病毒阳性（HPV+）口腔癌（OC），占口咽癌的70％以上 发现北美和欧洲的案件更具侵略性，而转移的趋势更高 与HPV负OC相比。人们认为这种侵略性与其本质有关 HPV感染触发的致癌机制。 HPV编码两个有效的Oncogenes E6和E7 灭活键肿瘤抑制剂PRB和p53，然后随后改变了口服中基因的表达光谱 上皮细胞。为了鉴定HPV肿瘤发生的分子机制，许多研究比较了 HPV+ OC对正常口服上皮，HPV阴性OC或其他癌症类型的（EPI）基因组谱。这些 研究已经使用不同的方法（转录组，基因组生成高通量测序数据集 和表观基因组）和细胞条件（正常，病毒感染和癌变）。但是，这些数据集是 由于缺乏可比较的分析平台无法有效询问它们，因此无法完全探索它们，尤其是在 在研究中，异质性和批处理效应都很高。我们建议利用我们的数据科学经验 以及密切的湿lab协作以执行综合分析，以识别HPV特异性生物标志物 HPV+ OC。我们建议从11项研究中整合（EPI）基因组下一代测序数据集 （加上将来有更多可用性），涉及3种数据类型，13种细胞系，3个病毒感染阶段和2个 解剖学上相似的站点。分析的核心是消除潜在的批处理效应和偏见 集成数据集并设置适当的控制以提名致癌生物标志物。为了验证发现，我们 提出了干和湿的实验，以评估候选生物标志物。拟议研究的见解 可以促进我们对口服生物学的理解，并有可能转化为HPV+ OC的新型治疗剂。