Pan-cancer genomic characterization of human papillomavirus associated tumors

人乳头瘤病毒相关肿瘤的泛癌基因组特征

• 批准号: 10612810
• 负责人: Jeremiah R. Holt
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612810
• 关键词: Affect; Anatomy; Anogenital cancer; Cancer Prognosis; Cervical; Chromosomes; Classification; Clinic; Clinical; Cytopathology; DNA Sequence Alteration; DNA sequencing; Data; Development; Disease-Free Survival; Ensure; Environment; Epithelial Cells; Event; Exhibits; Future; Genes; Genome; Genomic Instability; Genomics; Goals; Gynecologic; HPV analysis; HPV-High Risk; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Hybrids; In Vitro; Individual; Life Cycle Stages; Link; Location; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Maps; Mediating; Mentors; Methodology; Modeling; Molecular; Molecular Abnormality; Mutation; Oncogenic; Oncoproteins; Oral; Outcome; PI3K/AKT; PIK3CA gene; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Prognosis; Property; Proteins; Research Training; Residual state; Sample Size; Scientist; Smoking; Smoking Status; Somatic Mutation; Squamous cell carcinoma; Staging; Structure; TNM; TP53 gene; Techniques; Testing; Therapeutic; Training; Treatment outcome; Tumor Suppressor Proteins; Variant; Viral; Viral Genome; Viral Load result; Virus Integration; Work; cancer classification; cancer genomics; cancer type; career; chronic infection; clinical training; clinically relevant; cohort; driver mutation; genome-wide; genomic data; improved; improved outcome; in vivo; individualized medicine; malignant mouth neoplasm; mouth squamous cell carcinoma; neoplasm resource; next generation sequencing; novel; novel strategies; personalized care; personalized medicine; precision medicine; prognostic; targeted sequencing; training opportunity; tumor; tumorigenesis; tumorigenic; viral DNA

PROJECT SUMMARY/ABSTRACT Human papilloma virus (HPV) infection causes an estimated 610,000 human cancers globally every year. HPV accounts for nearly all cervical and anal squamous cell carcinomas, increasing rates of head and neck squamous cell carcinomas, and a subset of other anogenital squamous carcinomas – all with relatively heterogenous clinical outcomes due to a lack of personalized care. My goal is to use a pan-cancer cohort of patients to define the molecular heterogeneity shared across HPV-associated anatomic sites. Analyses that integrate many genomic variables across patient cohorts, powered by next-generation sequencing, have successfully ascertained genomic perturbations in individual tumor types. However, few studies have focused particularly on genomic changes across HPV(+) cancers of differing anatomical origin. Additionally, there is little genomic data available to analyze these differences in anogenital cancers. While large scale collaborative efforts to investigate the molecular landscape of head and neck cancers have been successful, the specific genomic changes and clinical outcomes attributable to HPV infection lack clarity due to smaller HPV(+) cohorts and confounders like smoking. The HPV lifecycle is tightly linked to differentiation of the epithelial cells it infects. The transformative potential of the oncogenic strains is classically attributed to expression of viral oncoproteins E6 and E7, which subsequently inactivate tumor suppressors TP53 and RB, respectively. However, while persistent infection with high-risk HPV types and expression of E6/E7 proteins are capable of cellular immortalization in vitro and are necessary in the formation of tumors, these events alone are insufficient for cancer development in vivo. Thus, viral and host genomic changes must occur alongside HPV infection. It is my hypothesis that the molecular heterogeneity of HPV-associated tumors is shared across anatomic sites and can be used to subclassify these cancers based on therapeutically meaningful pathways. To test this, integrative analyses of HPV(+) and HPV(-) tumors will be employed using hybrid-capture sequencing across extensive cohorts of cervical, oral, and anogenital tumors. Specifically, paired-end DNA sequencing using probes specific to hundreds of genes commonly involved in cancer will be used to identify potential driver somatic mutations and copy number alterations in these tumors (Aim I). Novel genomic changes determined here will then be examined in context with other known biologically pathways and molecular perturbations in HPV-associated cancers. Next, probes specific to the HPV genome will be used to assess viral properties such as strain, viral load, and integration events within and across tumor types (Aim II). Finally, the prognostic effect of oncogenic PIK3CA alterations will be determined through integration of clinical variables and overall survival using multivariate modeling (Aim III). This unique training opportunity and exemplary mentoring environment will ensure my complete development as a physician-scientist in clinical genomics working to identify novel means of subclassifying patients in order to tailor treatments and improve outcomes.

项目概要/摘要 据估计，人乳头瘤病毒 (HPV) 感染每年导致全球 610,000 例人类癌症。 HPV病毒 几乎所有宫颈和肛门鳞状细胞癌均由该癌引起，头颈部鳞状细胞癌的发病率不断增加 细胞癌和其他肛门生殖器鳞状细胞癌的一个子集——所有这些都具有相对异质性的临床 由于缺乏个性化护理而导致的结果。我的目标是使用泛癌症患者队列来定义 HPV 相关解剖部位之间存在分子异质性。综合多种分析 在下一代测序的支持下，跨患者群体的基因组变量已成功 确定个体肿瘤类型的基因组扰动。然而，很少有研究特别关注 不同解剖学起源的 HPV(+) 癌症的基因组变化。此外，还有很少 基因组数据可用于分析肛门生殖器癌症的这些差异。在大规模协作努力的同时 研究头颈癌的分子景观已经成功，特定的基因组 由于 HPV(+) 群体规模较小，因此 HPV 感染引起的变化和临床结果缺乏明确性 诸如吸烟之类的混淆因素。 HPV 生命周期与其感染的上皮细胞的分化密切相关。这 致癌菌株的转化潜力通常归因于病毒癌蛋白 E6 的表达 和E7，随后分别使肿瘤抑制因子TP53和RB失活。然而，在坚持的同时 高危 HPV 类型的感染和 E6/E7 蛋白的表达能够使细胞永生化 体外，并且是肿瘤形成所必需的，但仅这些事件不足以促进癌症的发展 体内。因此，病毒和宿主基因组变化必须与 HPV 感染同时发生。我的假设是 HPV 相关肿瘤的分子异质性在各个解剖部位之间是共有的，可以利用 根据具有治疗意义的途径对这些癌症进行细分。为了测试这一点，综合 将使用杂交捕获测序对 HPV(+) 和 HPV(-) 肿瘤进行广泛分析 宫颈、口腔和肛门生殖器肿瘤队列。具体来说，使用特异性探针进行双端 DNA 测序 数百个通常与癌症有关的基因将被用来识别潜在的驱动体细胞突变 这些肿瘤中的拷贝数变化（目标 I）。然后将检查此处确定的新基因组变化 与 HPV 相关癌症中其他已知的生物学途径和分子扰动相关。下一个， HPV 基因组特异性探针将用于评估病毒特性，例如毒株、病毒载量和 肿瘤类型内和肿瘤类型之间的整合事件（目标 II）。最后，致癌PIK3CA的预后作用 将通过使用多变量整合临床变量和总体生存来确定改变 建模（目标 III）。这种独特的培训机会和模范指导环境将确保我 作为一名临床基因组学医师科学家的全面发展，致力于寻找新的方法 对患者进行细分，以便调整治疗方案并改善结果。