The role of germline and somatic DNA mutations in oral and oropharyngeal cancers

项目概要/摘要 头颈部的大多数癌症是鳞状细胞癌（HNSCC），并且大多数影响口腔癌。 腔或咽。吸烟和饮酒是主要的风险因素， 大约三分之二的案件。口腔感染人乳头瘤病毒（HPV）是一种重要的 口咽癌（OPC）发展的独立风险因素;只有6%的其他HNSCC部位 与HPV有关。HPV相关OPC的发病率正在增加，尤其是在美国和欧洲。 有趣的是，可能是由于病因学的差异和肿瘤特征的相关差异，HPV- 阳性[HPV（+）]肿瘤比HPV阴性[HPV（-）]肿瘤具有更有利的结果。最近的一项大型 来自该组的全基因组关联（GWA）研究鉴定了HNSCC的多个新的易感基因座， 特别是人白细胞抗原（HLA）区在OPC中的重要作用。此外，最近 完整的肿瘤基因组分析工作提供了关于体细胞改变的重要信息， 存在于HNSCC中。然而，只有有限数量的HPV（+）肿瘤被纳入，这些研究 由于临床研究的有限性， 和可用的结果数据。提高对口腔癌（OC）遗传因素的认识， OPC风险和结局，我们将利用来自5个注释良好的研究人群的样本和数据：（目标1） 对2,028例OPC病例进行完整的HPV分析，以评估生殖系变异之间的关系， 和HPV（+）OPC的风险;（目的2）进行全外显子组， 对2,000个代表性肿瘤（1,000个OC，1,000个OPC）进行靶向测序，以进一步阐明驱动因素 OC和OPC的突变和潜在的治疗靶点，并阐明相关的潜在机制， 生活方式和感染暴露与发展这两种癌症;和（目标3）利用现有的结果数据 对这2,000名患者进行研究，以评估OC和OPC的体细胞改变在结局中的作用， OC和OPC生存模型，并阐明吸烟在HPV（+）OPC结局中的作用。

PROJECT SUMMARY/ABSTRACT Most cancers of the head and neck are squamous cell carcinomas (HNSCC) and the majority affects the oral cavity or pharynx. Tobacco use and alcohol consumption are the major risk factors and together account for approximately two-thirds of the cases. Oral infection with human papillomavirus (HPV) is an important independent risk factor for the development of oropharyngeal cancer (OPC); only 6% of other HNSCC sites are associated with HPV. Incidence of HPV-related OPC is increasing, most notably in the U.S. and Europe. Interestingly, and likely due to differences in etiology and related differences in tumor characteristics, HPV- positive [HPV(+)] tumors have a more favorable outcome than HPV-negative [HPV(-)] tumors. A recent large genome-wide association (GWA) study from this group identified multiple novel susceptibility loci for HNSCC, and in particular a strong role for the human leukocyte antigen (HLA) region in OPC. Further, recently completed tumor genome profiling efforts have provided important information on the somatic alterations present in HNSCC. However, only limited numbers of HPV(+) tumors were included and these studies have offered little insights into the clinical relevance of the identified alterations due to the limited nature of clinical and outcome data available. To improve understanding of the genetic factors involved in oral cancer (OC) and OPC risk and outcome, we will utilize samples and data from 5 well-annotated study populations to: (Aim 1) complete HPV analysis of 2,028 OPC cases in order to evaluate the relationship between germline variants, and in particular variants in the HLA region, and risk of HPV(+) OPC; (Aim 2) perform whole exome and targeted sequencing on 2,000 representative tumors (1,000 OCs, 1,000 OPCs) to further elucidate the driver mutations and potential therapeutic targets in OC and OPC, and to clarify potential mechanisms associated with lifestyle and infectious exposures for developing both cancers; and (Aim 3) utilize available outcome data on these 2,000 patients to evaluate the role of somatic alterations in OC and OPC in outcome, build prediction models for OC and OPC survival, and clarify the role of smoking in HPV(+) OPC outcome.