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

项目摘要/摘要 头颈部鳞状细胞癌(HNSCC)的存活率很低，非洲人之间存在种族差异 美国人(AFAM)和欧洲美国人(EuAM)几十年来一直是一致的。2008-2014，5年 据报道，在非霍奇金淋巴瘤患者中，口腔癌和咽癌的相对存活率为49.4%，而 EuAM中占66.6%。同样，喉癌的5年相对存活率在2003年的AfAM中为51.3% 相比之下，EuAM的这一比例为61.8%。文献表明，生存不良可能与晚期有关。 这是由于筛查率较低、社会经济地位(SES)和其他护理障碍造成的。 然而，我们的初步数据表明，仅靠这些因素可能不能提供完整的解释。我们 研究表明，AFAM的复发、第二原发癌或转移的风险高于 在匹配了患者的年龄和吸烟量，并调整了性别、癌症家族史、酒精后，EuAM 使用、SES、保险、诊断阶段和治疗方式。这些发现表明，除了临床 而社会经济因素、宿主因素，如遗传因素，也可能导致生存差异。标准 HNSCC的治疗采用综合疗法，涉及DNA损伤剂，如 放疗(RT)和以铂为基础的化疗(PbC)。对DNA的治疗敏感性降低 损伤剂通常被认为是通过表达DNA损伤反应(DDR)基因来修复DNA损伤 在癌症组织中。我们对口腔癌和喉癌组织(OCLxC)进行了基因组分析 癌症基因组图谱(TCGA)中的患者。遗传血统对DDR基因表达的影响 对316名患者的基因进行了评估。在调整了基因甲基化、拷贝数变异和种群后 分层，五个祖先信息标记(AIMS)与改变的mRNA表达有关 DDR基因聚合酶β(POLb)，其中1)POLb在AFAM患者中高表达 有一个或两个非洲血统等位基因的EuAM患者和接受RT/PbC治疗的患者的比较 这些基因座(纯合子或杂合子)的总存活率较低(~21%)，疾病- 自由存活率(~22%)与这些基因座上有两个欧洲血统等位基因的患者形成对比。高架 POLB的表达调节细胞DNA修复能力和DNA复制，从而为肿瘤提供 对RT/PbC耐药。因此，我们将检验这一假设，即遗传祖先对 POLB的表达导致黑人和白人OCLxC患者治疗后生存率的差异 RT/PbC，由增强的核和线粒体DNA修复能力和致癌样复制物介导 由于POLBOVER表达式而导致的状态。使用涉及分子流行病学的新方法，结合 基本的肿瘤细胞和分子生物学，我们将证实我们的初步发现，研究其功能 遗传祖先对POLB表达的意义及AFAM和EuAM的生存差异 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.