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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要头颈鳞状细胞癌 (HNSCC) 的生存率很低，非洲人之间存在种族差异美国人（AfAm）和欧洲美国人（EuAm）从2008年到2014年，连续5年保持一致。据报道，AfAm 患者的口腔癌和咽癌相对生存率为 49.4%，而同样，EuAms 中喉癌的 5 年相对生存率为 51.3%。与此相反，欧盟国家的这一比例为 61.8%。文献表明，生存率低可能与晚期有关。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，仅这些因素可能无法提供完整的解释。研究表明，与 AfAm 相比，AfAm 的复发、第二原发癌或转移的风险更高 EuAm 在匹配患者的年龄和吸烟剂量并调整性别、癌症家族史、酒精后使用、SES、保险、诊断阶段和治疗方式这些发现表明与临床不同。和社会经济因素、遗传等宿主因素也可能导致生存差异。 HNSCC 的治疗采用联合疗法，其中涉及 DNA 损伤剂，例如放疗 (RT) 和铂类化疗 (PbC) 降低治疗对 DNA 的敏感性。损伤剂通常归因于表达的 DNA 损伤反应 (DDR) 基因对 DNA 损伤的修复我们对口腔癌和喉癌 (OCLxC) 的组织进行了基因组分析。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。在调整基因甲基化、拷贝数变异和群体后，对 316 名患者的基因进行了评估。分层中，五个祖先信息标记 (AIM) 与 mRNA 表达的改变相关 DDR 基因聚合酶 β (POLB)，其中 1) 在 AfAm 患者中观察到 POLB 表达较高与 EuAm 患者和 2) 具有一或两个非洲血统等位基因且接受 RT/PbC 治疗的患者进行比较这些基因位点（纯合或杂合基因型）的总生存率较低（~21%），并且疾病- 与这些基因位点具有欧洲血统等位基因的患者相比，自由生存率（~22%）升高。 POLB 的表达调节细胞 DNA 修复能力和 DNA 复制，从而提供肿瘤因此，我们将检验遗传血统导致差异的假设。 POLB 的表达导致黑人和白人 OCLxC 患者的生存率存在差异 RT/PbC，由增强的核和线粒体 DNA 修复能力和致癌样复制介导状态由于 POLB 过度表达使用涉及分子流行病学结合的新方法。基础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 之间生存差异的重要性 OCLxC 患者。