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.

项目概要/摘要 宫颈癌是女性最常见的癌症之一，标准治疗失败 局部晚期宫颈癌 (LACC) 的护理 (SOC) 放化疗 (CRT) 高达 30-50%。 由于复发性和转移性疾病无法治愈或发现得太晚而无法治疗，因此迫切需要 需要治疗前生物标志物来识别有 CRT 治疗失败风险的患者和治疗后 早期检测 LACC 复发和转移的生物标志物。 TCGA 努力建立治疗前生物标志物 使用人类基因对宫颈癌进行分子分层未能与患者结果相关联。上 另一方面，我们最近证明 HPV 基因型和 HPV 选择性剪接影响 LACC 复发 以及 CRT 后的生存率。在我们的初步数据中，我们还确定了 HPV 基因组结构的多样性 (HPV-GS)，包括涉及可变剪接 HPV 外显子的 HPV-人类基因融合，影响人类 癌基因表达。我们假设 LACC 中 HPV 基因组结构特征的差异 患者可能代表着开发 LACC SOC CRT 生物标志物的有价值的临床测序应用。为了 治疗后标记物，我们目前使用 3-6 个月的 18F-氟脱氧葡萄糖 PET/CT (FDG-PET) 图像来 定义代谢反应，这在我们之前的出版物中已显示，用于预测术后失败的模式 宫颈癌的放射治疗。我们假设HPV基因组特征可以作为后治疗 用于 LACC 复发和转移检测的生物标志物更准确且可更早检测 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 的变异来开发 基于我们的专业知识，开发了一系列新型 HPV-GS 分析工具，为临床治疗前生物标志物 HPV 基因组学和人类结构变异。 HPV 特征将从匹配的 DNA 中提取并 RNA 测序数据及其预后值将使用我们宫颈肿瘤库中的样本进行测试 LACC 患者统一接受治愈性 CRT 治疗。其次，我们将检查 CRT 是否诱发 LACC 克隆进化可用于识别治疗耐药的 HPV-GS 作为治疗生物标志物。一部有深度的小说 靶向测序方法将用于单核苷酸变异 (SNV) 和 HPV-GS 来识别 LACC 亚克隆并在克隆进化的背景下拟合 HPV-GS。我们还将研究 HPV 的机制 使用克隆生存测定和其他标准测定进行人类基因融合。最后，我们将使用我们经过验证的 高度灵敏且灵活的 CAPP-Seq 技术可评估循环肿瘤 DNA (ctDNA) 是否可以 用于开发 HPV-GS 检测以进行早期诊断和 CRT 后复发检测。我们期望结合 SNV 和 HPV-GS 都将带来优于单独使用单一类型特征的优化应用程序。 总而言之，我们期望在 CRT 背景下对 HPV-GS 生物标志物进行基因组和机制研究。 诱导的 LACC 进化将产生一系列优化的治疗前和复发生物标志物 在临床上应用个性化替代治疗方案。