Pan-cancer genomic characterization of human papillomavirus associated tumors

项目概要/摘要 人类乳头状瘤病毒（HPV）感染每年在全球造成约61万例人类癌症。HPV 几乎占所有宫颈和肛门鳞状细胞癌，增加率的头部和颈部鳞状细胞癌， 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特征。 这是由于缺乏个性化的护理。我的目标是使用一个泛癌症患者队列来定义 HPV相关解剖部位的分子异质性。分析整合了许多 在下一代测序的支持下，跨患者队列的基因组变量已成功 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 不同解剖学起源的HPV（+）癌症的基因组变化。此外，几乎没有 基因组数据来分析肛门生殖器癌中的这些差异。虽然大规模的合作努力 研究头颈癌的分子景观已经成功，特定的基因组 由于HPV（+）队列较小，HPV感染引起的变化和临床结局缺乏明确性， 混杂因素如吸烟。HPV的生命周期与其感染的上皮细胞的分化密切相关。的 致癌株的转化潜力通常归因于病毒癌蛋白E6的表达 和E7，其随后分别抑制肿瘤抑制子TP 53和RB。然而，虽然坚持 感染高危型HPV和表达E6/E7蛋白能够使细胞永生化， 在体外和肿瘤的形成是必要的，这些事件本身是不够的癌症发展 in vivo.因此，病毒和宿主基因组的变化必须与HPV感染同时发生。我假设 HPV相关肿瘤的分子异质性在解剖部位共有， 根据有治疗意义的途径对这些癌症进行细分。为了验证这一点， HPV（+）和HPV（-）肿瘤的分析将使用杂交捕获测序， 宫颈、口腔和肛门生殖器肿瘤的队列。具体地，使用特异性探针的双端DNA测序 到数百个通常参与癌症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改变（Aim I）。新的基因组变化确定在这里，然后将检查 与HPV相关癌症中其他已知的生物学途径和分子扰动有关。接下来， HPV基因组特异性探针将用于评估病毒特性，如毒株、病毒载量和 在肿瘤类型内和跨肿瘤类型的整合事件（Aim II）。最后，致癌PIK 3CA的预后作用 将通过使用多变量方法整合临床变量和总生存率来确定变化。 建模（Aim III）。这种独特的培训机会和示范性的指导环境将确保我 作为临床基因组学的医生-科学家，完成开发工作，以确定新的方法， 对患者进行细分，以调整治疗方案并改善结果。

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.