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

项目摘要/摘要 大多数头颈部癌症是鳞状细胞癌(HNSCC)，大多数累及口腔 空洞或咽部。吸烟和饮酒是主要的危险因素，它们加在一起是 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)发展的独立危险因素；只有6%的其他HNSCC部位是 与HPV有关。与HPV相关的OPC的发病率正在上升，最明显的是在美国和欧洲。 有趣的是，很可能是由于病因的不同和相关肿瘤特征的差异，HPV- HPV阳性[HPV(+)]肿瘤比HPV阴性[HPV(-)]肿瘤预后更好。最近的一次大型 来自该小组的基因组范围关联(GWA)研究确定了HNSCC的多个新的易感基因座， 尤其是人类白细胞抗原(HLA)区域在OPC中的强大作用。更进一步，最近 已完成的肿瘤基因组图谱工作提供了有关体细胞变化的重要信息 出现在HNSCC。然而，只有数量有限的HPV(+)肿瘤被包括在内，这些研究已经 由于临床性质有限，对已识别的改变的临床相关性几乎没有提供深入的见解 以及可用的结果数据。提高对口腔癌(OC)和口腔癌相关遗传因素的了解 OPC风险和结果，我们将利用来自5个有良好注释的研究人群的样本和数据来：(目标1) 完成对2,028例OPC患者的HPV分析，以评估生殖系变异之间的关系， 尤其是人类白细胞抗原区域的变异，以及HPV(+)OPC的风险；(目标2)执行整个外显子组和 对2,000个有代表性的肿瘤(1,000个OCs，1,000个OPC)进行靶向测序，以进一步阐明驱动因素 OC和OPC中的突变和潜在的治疗靶点，并阐明相关的潜在机制 生活方式和感染性暴露导致这两种癌症的发生；以及(目标3)利用现有的结果数据 对这2,000名患者评估OC和OPC的躯体改变在预后中的作用，建立预测 OC和OPC存活的模型，并阐明吸烟在HPV(+)OPC预后中的作用。

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.