HPV genomic structure in cervical cancer radiation response and recurrence detection

HPV基因组结构在宫颈癌放射反应和复发检测中的作用

• 批准号: 10634999
• 负责人: Jin Zhang
• 金额: $ 50.02万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634999
• 关键词: Address; Adenocarcinoma; Adjuvant; Adjuvant Chemotherapy; Affect; Aftercare; Alternative Splicing; Biological Assay; Biological Markers; Cancer Patient; Cancer Personalized Profiling by Deep Sequencing; Cervix Neoplasms; Cessation of life; Cisplatin; Clinic; Clinical; Clinical Trials; Clonal Evolution; DNA; DNA sequencing; Data; Detection; Diagnosis; Disease; Early Diagnosis; Early Intervention; Episome; Evolution; Exons; Failure; Gene Expression; Gene Expression Profile; Gene Frequency; Gene Fusion; Genes; Genome; Genomics; Genotype; Goals; HPV-High Risk; Human; Human Chromosomes; Human Papillomavirus; Human papilloma virus infection; Hysterectomy; Image; Immunotherapy; Keratin; Local Therapy; Machine Learning; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Manuals; Measures; Mesenchymal; Metabolic; Metastatic/Recurrent; Molecular; Monitor; Neoplasm Metastasis; Newly Diagnosed; Nucleic Acid Regulatory Sequences; Oncogenes; Outcome; Patient-Focused Outcomes; Patients; Pattern; Plasma; Population; Prediction of Response to Therapy; Publications; RNA; Radiation therapy; Radiosensitization; Randomized, Controlled Trials; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Reporting; Research; Resistance; Risk; Risk Assessment; Sampling; Series; Single Nucleotide Polymorphism; Staging; Staging System; Stratification; Structure; Subgroup; Survival Rate; Targeted Radiotherapy; Technology; Testing; The Cancer Genome Atlas; Time; Treatment Failure; Treatment Protocols; Tumor Bank; Validation; Variant; Visualization; Woman; X-Ray Computed Tomography; alternative treatment; annotation system; cancer diagnosis; cancer genomics; cancer recurrence; cancer survival; cervical cancer prevention; chemoradiation; chemotherapy; chronic infection; clinical biomarkers; clinical sequencing; clinically actionable; cohort; experience; flexibility; fluorodeoxyglucose positron emission tomography; genetic variant; genomic data; high risk; human papilloma virus oncogene; improved; improved outcome; malignant breast neoplasm; neoantigens; novel; outcome prediction; palliative; prognostic value; programmed cell death ligand 1; radiation response; research clinical testing; response; risk stratification; standard of care; targeted sequencing; therapy resistant; tool; transcriptome sequencing; treatment response; tumor; tumor DNA; vaccine acceptance

PROJECT SUMMARY/ABSTRACT Cervical cancer is one of the most common cancer diagnoses among women, and treatment failure of standard of care (SOC) chemoradiation therapy (CRT) for locally advanced cervical cancer (LACC) is as high as 30-50%. Since recurrent and metastatic diseases are not curable or detected too late to be treatable, there is a pressing need for pre-treatment biomarkers to identify patients at risk of CRT treatment failure and post-treatment biomarkers to detect LACC recurrence and metastasis early. TCGA’s effort to establish pre-treatment biomarkers for cervical cancer by molecular stratification using human genes failed to associate to patient outcomes. On the other hand, we recently demonstrated that HPV genotypes and HPV alternative splicing affect LACC recurrence and survival after CRT. In our preliminary data, we additionally identified a diversity of HPV genomic structures (HPV-GS), including HPV-human gene fusions involving alternative spliced HPV exons, that affect human oncogene expression. We hypothesize that the variance of HPV genomic structural features among LACC patients may represent a valuable clinical sequencing application to develop LACC SOC CRT biomarkers. For post-treatment markers, we currently use F-fluorodeoxyglucose PET/CT (FDG-PET) images at 3–6 months to define metabolic response, which was shown in our previous publications to predict patterns of failure after radiotherapy for cervical cancer. We hypothesize that HPV genomic features can serve as post-treatment biomarkers for LACC recurrence and metastasis detection that are both more accurate and detectable at earlier timepoints. To achieve these goals, we will first test whether variance in HPV-GS can be utilized to develop a clinical pre-treatment biomarker by developing a series of novel HPV-GS analysis tools based on our expertise in both HPV genomics and human structural variants. HPV features will be extracted from matched DNA and RNA sequencing data, and their prognostic values will be tested using samples from our cervical tumor bank of LACC patients uniformly treated with curative-intent CRT. Second, we will examine whether CRT-induced LACC clonal evolution can be used to identify treatment-resistant HPV-GS as on-treatment biomarkers. A novel deep targeted sequencing approach will be used on single-nucleotide variants (SNV) and HPV-GS to identify LACC subclones and fit HPV-GS in the context of clonal evolution. We will also examine the mechanisms of HPV- human gene fusions using clonogenic survival assays and other standard assays. Last, we will use our proven highly-sensitive and flexible CAPP-Seq technology to evaluate whether circulating tumor DNA (ctDNA) can be used to develop HPV-GS tests for early diagnosis and post-CRT recurrence detection. We expect combining both SNVs and HPV-GS will result in an optimized application superior to using single types of features alone. Taken together, we expect our genomic and mechanistic research on HPV-GS biomarkers in the context of CRT- induced LACC evolution will create a series of optimized pre-treatment and recurrence biomarkers that can be applied in the clinic for personalized alternative treatment regimens.

项目摘要/摘要 宫颈癌是女性最常见的癌症诊断之一，治疗失败的标准 护理(SOC)放化疗(CRT)治疗局部晚期宫颈癌(LACC)的比例高达30%-50%。 由于复发和转移性疾病不能治愈，或者发现得太晚而无法治愈，因此有一个紧迫的问题 需要治疗前生物标志物来确定CRT治疗失败和治疗后的风险 早期发现LACC复发和转移的生物标志物。TCGA为建立治疗前生物标志物所做的努力 通过使用人类基因进行分子分层的宫颈癌未能与患者的预后相关联。论 另一方面，我们最近证明了HPV基因分型和HPV选择性剪接影响LCC复发 以及CRT后的存活率。在我们的初步数据中，我们还鉴定了HPV基因组结构的多样性。 (HPV-GS)，包括涉及HPV外显子选择性剪接的HPV-人类基因融合，影响人类 癌基因表达。我们假设人类乳头状瘤病毒基因组结构特征在LACC之间的差异 患者可能代表着开发LACC SOC CRT生物标记物的有价值的临床测序应用。为 治疗后标志物，我们目前在3-6个月时使用F-氟代脱氧葡萄糖PET/CT(FDG-PET)图像 定义代谢反应，这在我们以前的出版物中显示过，以预测在 宫颈癌的放射治疗。我们假设人乳头瘤病毒基因组特征可以作为治疗后的 更准确、更早检测LCC复发和转移的生物标志物 时间点。为了实现这些目标，我们将首先测试是否可以利用HPV-GS的差异来开发一种 基于我们的专业知识开发一系列新型HPV-GS分析工具的临床前生物标志物 在人乳头瘤病毒基因组学和人类结构变异中。将从匹配的DNA中提取HPV特征并 Rna测序数据，以及它们的预后价值将使用我们的宫颈肿瘤库的样本进行测试。 LACC患者统一接受根治性CRT治疗。第二，我们将研究CRT诱导的LACC 克隆进化可用于识别耐药HPV-GS作为治疗中的生物标记物。一部深沉的小说 将在单核苷酸变异(SNV)和HPV-GS上使用靶向测序方法来识别LACC 亚克隆和适合克隆进化的HPV-GS。我们亦会探讨人类乳头状瘤病毒的机制- 使用克隆生存分析和其他标准分析进行人类基因融合。最后，我们将使用经过验证的 高灵敏灵活的CAPP-Seq技术评价循环肿瘤DNA(CtDNA)能否 用于开发HPV-GS检测，用于早期诊断和CRT后复发检测。我们期待着合并 SNV和HPV-GS都将产生一个优化的应用程序，优于单独使用单一类型的功能。 综上所述，我们期待着我们在CRT背景下对HPV-GS生物标记物的基因组和机制研究。 诱导LACC进化将创建一系列优化的治疗前和复发生物标记物，这些标记物可以 应用于临床进行个性化替代治疗方案。