Pan-cancer genomic characterization of human papillomavirus associated tumors

项目摘要/摘要 人类乳头瘤病毒(HPV)感染每年在全球造成约61万例人类癌症。人类乳头瘤病毒 导致几乎所有的宫颈和肛门鳞状细胞癌，增加头和颈部鳞状细胞癌的比率 细胞癌和其他肛门生殖器鳞癌的子集--都具有相对不同的临床特征 由于缺乏个性化护理而导致的后果。我的目标是使用泛癌患者队列来定义 HPV相关解剖部位的分子异质性是相同的。分析整合了多个 在下一代测序的支持下，患者队列中的基因组变量已经成功 确定了个体肿瘤类型中的基因组扰动。然而，很少有研究特别关注 关于不同解剖来源的HPV()癌症的基因组变化。此外，几乎没有 基因组数据可用于分析肛门癌的这些差异。虽然大规模的合作努力 研究头颈部癌症的分子图谱已经成功，特定的基因组 由于HPV()队列较小，可归因于HPV感染的变化和临床结果尚不清楚 混血儿喜欢抽烟。HPV的生命周期与其感染的上皮细胞的分化密切相关。这个 致癌菌株的转化潜力经典地归因于病毒癌蛋白E6的表达 和E7，随后分别使肿瘤抑制基因TP53和RB失活。然而，尽管坚持不懈 高危型HPV感染和E6/E7蛋白的表达能够使细胞永生化 在体外，这些事件是肿瘤形成所必需的，这些事件本身不足以促进癌症的发展 在活体内。因此，病毒和宿主基因组的变化必须与HPV感染同时发生。我的假设是 HPV相关肿瘤的分子异质性在不同的解剖部位共享，并可用于 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 对HPV()和HPV(-)肿瘤的分析将使用混合捕获测序 宫颈、口腔和肛门肿瘤的队列。具体地说，使用特定探针的配对末端DNA测序 到数百个与癌症有关的基因将被用来识别潜在的驱动体细胞突变和 这些肿瘤的拷贝数改变(目标I)。然后将检查在这里确定的新的基因组变化 在其他已知的生物学途径和HPV相关癌症的分子扰动的背景下。下一首, 针对HPV基因组的探针将用于评估病毒特性，如毒株、病毒载量和 肿瘤类型内部和之间的整合事件(AIM II)。最后，致癌基因PIK3CA的预后作用 改变将通过综合临床变量和使用多变量的总体生存来确定 建模(AIM III)。这种独特的培训机会和模范的指导环境将确保我的 作为一名临床基因组学医生-科学家的完整发展，致力于寻找新的方法 对患者进行细分，以便进行量身定制的治疗和改善结果。

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.