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

研究遗传血统对口腔癌和喉癌生存差异的影响

• 批准号: 10608044
• 负责人: Camille C. Ragin
• 金额: $ 57.89万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608044
• 关键词: Affect; African; African American; African American population; African ancestry; Age; Alcohol consumption; Alcohols; Alleles; American; Biological; Biological Factors; Black race; Cancer Patient; Cessation of life; Characteristics; Clinical; Combined Modality Therapy; Copy Number Polymorphism; DNA Damage; DNA Polymerase beta; DNA Repair; DNA biosynthesis; DNA lesion; DNA replication fork; Data; Development; Diagnosis; Disease; Disease-Free Survival; Disparity; Dose; European; European ancestry; Family Cancer History; Frequencies; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomic Instability; Genomics; Genotype; Head and Neck Squamous Cell Carcinoma; Heterozygote; Human Papillomavirus; Incidence; Institution; Insurance; Integration Host Factors; Investigation; Larynx; Literature; Malignant Neoplasms; Malignant neoplasm of larynx; Malignant neoplasm of pharynx; Mediating; Messenger RNA; Methylation; Mitochondrial DNA; Modality; Molecular Biology; Molecular Epidemiology; Neoplasm Metastasis; Newly Diagnosed; Nuclear; Oncogenes; Oncogenic; Operative Surgical Procedures; Oral cavity; Oropharyngeal; Pathway interactions; Patients; Pharyngeal structure; Phenotype; Platinum; Play; Polymerase; Polymerase Gene; Prognosis; Radiation therapy; Recording of previous events; Recurrence; Reporting; Resistance; Risk; Role; Second Primary Cancers; Smoking; Socioeconomic Factors; Socioeconomic Status; Stage at Diagnosis; Survival Rate; Testing; The Cancer Genome Atlas; Time; Tissue Microarray; Tissues; Tobacco; Tumor Cell Biology; Work; barrier to care; cancer survival; chemotherapy; differential expression; experimental study; genomic locus; hazard; health disparity; high risk; low socioeconomic status; mRNA Expression; mortality risk; novel; novel strategies; oral tissue; overexpression; population stratification; prognostic; protein expression; racial disparity; replication stress; response; screening; sex; standard care; survival disparity; tumor

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.

项目摘要/摘要 头部和颈部方形细胞癌（HNSCC）的生存差，非洲人之间的种族差异 美国人（AFAM）和欧洲人（EUAM）数十年来一直保持一致。从2008 - 2014年为5年 据报道，来自口腔和咽癌的相对生存率在AFAM中为49.4％ EUAM中的66.6％。同样，喉癌的5年相对存活率为51.3％ 在EUAM中与61.8％的形成对比。文献表明，生存差可能与后期有关 诊断归因于较低的筛查率，社会经济状况（SES）和其他护理障碍。 但是，我们的初步数据表明，仅这些因素可能无法提供完整的解释。我们 已经表明，与AFAM相比，AFAM复发，第二个原发性癌症或转移的风险更高 EUAM与年龄和吸烟剂量相匹配并调整性别，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，除临床以外 和社会经济因素，遗传学等宿主因素也可能有助于生存分布。标准 HNSCC的治疗利用了涉及DNA破坏剂的合并模式疗法，例如 放疗（RT）和基于铂的化学疗法（PBC）。降低对DNA的治疗敏感性 损害剂通常归因于通过表达的DNA损伤响应（DDR）基因修复DNA病变 在癌组织中。我们对口腔和喉癌（OCLXC）的组织进行了基因组分析 癌症基因组地图集（​​TCGA）的患者。遗传血统对DDR基因表达的影响 在316名患者中评估了基因。调整基因甲基化后，拷贝数变化和种群 分层，五个祖先信息标记（AIM）与mRNA表达的改变有关 DDR基因聚合酶β（POLB），其中1）在AFAM患者中观察到较高的POLB表达 与EUAM患者和2）用RT/PBC用一两个非洲血统治疗的患者进行比较 （纯合子或杂合基因型）在这些遗传性局部的总生存率较低（约21％）和疾病 - 与这些遗传基因座的两个欧洲血统等位基因的患者相比，自由生存（约22％）。高架 POLB的表达调节细胞DNA修复能力和DNA复制，可提供肿瘤 对RT/PBC的阻力。因此，我们将检验以下假设，即遗传血统有助于差异 POLB的表达导致黑人和白色OCLXC患者的生存差异 RT/PBC，通过增强的核和线粒体DNA修复能力和致癌性复制性介导 状态由于polb过度表达。使用涉及分子流行病学的新方法 碱性肿瘤细胞和分子生物学，我们将确认我们的初步发现，研究功能 遗传血统对POLB表达以及AFAM和EUAM之间的存活分布的重要性 OCLXC患者。