Investigating genetic ancestry influences on oral cavity and laryngeal cancer survival disparities

项目总结/摘要 头颈部鳞状细胞癌（HNSCC）的生存率很低，非洲人之间的种族差异 美国人（AfAm）和欧洲美国人（EuAm）几十年来一直保持一致。2008-2014年，5年 据报道，口腔癌和咽癌的相对存活率在AfAm中为49.4%， 66.6%的欧盟成员国。同样地，在2009年，喉癌的5年相对生存率为51.3%。 而EuAms为61.8%。文献表明，生存率低可能与晚期 诊断归因于较低的筛查率，社会经济地位（SES）和其他护理障碍。 然而，我们的初步数据表明，这些因素本身可能无法提供完整的解释。我们 已经表明，复发的风险，第二原发癌或转移是较高的AfAm相比， EuAm在匹配患者年龄和吸烟剂量并调整性别，癌症家族史，酒精 使用、SES、保险、诊断阶段和治疗方式。这些发现表明，除了临床 和社会经济因素，宿主因素如遗传也可能造成生存差异。标准 HNSCC的治疗利用涉及DNA损伤剂的组合形式疗法， 放疗（RT）和基于铂的化疗（PbC）。降低对DNA的治疗敏感性 损伤因子通常归因于通过表达的DNA损伤反应（DDR）基因修复DNA损伤。 在癌组织中。我们对口腔癌和喉癌（OCLxC）组织进行了基因组分析。 癌症基因组图谱（TCGA）遗传血统对DDR基因表达的影响 在316例患者中进行了基因评估。在调整了基因甲基化、拷贝数变异和群体后， 分层，五个祖先信息标记物（AIM）与改变的mRNA表达相关， DDR基因聚合酶β（POLB），其中1）在AfAm患者中观察到POLB的较高表达， 与EuAm患者和2）用RT/PbC治疗的具有一个或两个非洲血统等位基因的患者的比较 （纯合或杂合基因型）在这些遗传位点的总生存率较低（~21%），疾病- 与在这些遗传基因座上具有两个欧洲血统等位基因的患者相比，无瘤生存率（~22%）。升高 POLB的表达调节细胞DNA修复能力和DNA复制， 抗RT/PbC。因此，我们将测试遗传祖先有助于差异的假设， POLB的表达导致黑人和白色OCLxC患者之间的生存差异， RT/PbC，由增强的核和线粒体DNA修复能力和致癌样复制介导 由于POLB过度表达而导致的状态。使用新的方法，包括分子流行病学结合 基础肿瘤细胞和分子生物学，我们将证实我们的初步研究结果，研究功能， 遗传血统对POLB表达和AfAm与EuAm之间生存差异的意义 OCLxC患者。

PROJECT SUMMARY/ABSTRACT Survival from Head and Neck Squamous Cell Carcinoma (HNSCC) is poor, and a racial disparity between African Americans (AfAm) and European Americans (EuAm) has been consistent for decades. From 2008-2014, 5-year relative survival from oral cavity and pharyngeal cancers is reported to be 49.4% among AfAms in contrast to 66.6% among EuAms. Similarly, 5-year relative survival for laryngeal cancer was 51.3% among AfAms in contrast to 61.8% among EuAms. The literature suggests that poor survival may be related to late-stage diagnosis that is attributed to lower screening rates, socioeconomic status (SES) and other barriers to care. However our preliminary data suggest that these factors alone may not provide a complete explanation. We have shown that the risk of recurrence, second primary cancer or metastasis was higher for AfAm compared to EuAm after matching patients on age and smoking dose and adjusting for sex, family history of cancer, alcohol use, SES, insurance, stage at diagnosis, and treatment modality. These findings suggest that other than clinical and socioeconomic factors, host factors such as genetics may also contribute to survival disparities. Standard treatment of HNSCC utilizes combined-modality therapy that involves DNA damaging agents such as radiotherapy (RT) and platinum-based chemotherapy (PbC). A reduction of treatment sensitivity to DNA damaging agents are often attributed to repair of DNA lesions by DNA damage response (DDR) genes expressed in cancer tissues. We performed genomic analyses of tissues from oral cavity and laryngeal cancer (OCLxC) patients in The Cancer Genome Atlas (TCGA). The impact of genetic ancestry on gene expression of DDR genes was evaluated in 316 patients. After adjusting for gene methylation, copy number variation and population stratification, five ancestry informative markers (AIMs) were associated with altered mRNA expression of the DDR gene Polymerase β (POLB) where 1) higher expression of POLB was observed among AfAm patients in comparison to EuAm patients and 2) patients treated with RT/PbC with one or two African ancestry alleles (homozygous or heterozygous genotypes) at these genetic loci had lower overall survival (~21%) and disease- free survival (~22%) in contrast to patients with both European ancestry alleles at these genetic loci. Elevated expression of POLB modulates cellular DNA repair capacity and DNA replication that would provide tumor resistance to RT/PbC. Therefore we will test the hypothesis that genetic ancestry contributes to differences in expression of POLB resulting in differences in survival between Black and White OCLxC patients treated with RT/PbC, mediated by enhanced nuclear and mitochondrial DNA repair capacity and an oncogenic-like replicative state due to POLB over expression. Using novel approaches that involve molecular epidemiology combined with basic tumor cell and molecular biology, we will confirm our preliminary findings, investigate the functional significance of genetic ancestry on POLB expression and on survival disparities between AfAm and EuAm OCLxC patients.