Polymorphism and mutation spectrum in minorities with non-small cell lung cancer

描述(由申请人提供)：本申请涉及广泛的挑战领域(09)健康差距和具体的挑战主题，09-CA-104：癌症健康差距中的基础癌症研究。标题：少数非小细胞肺癌患者的基因多态性和突变谱肺癌是美国癌症相关死亡的主要原因。尽管存在相似的风险因素，但非洲裔美国人的肺癌发病率和死亡率高于其他人群。大量研究表明，遗传性和获得性遗传损伤对肺癌的发病风险和靶向治疗的结果和疗效都有重要影响。例如，表皮生长因子受体(EGFR)信号通路在非小细胞肺癌的发生、发展和侵袭过程中起重要作用。EGFR及其下游靶基因的多态和获得性突变的种族差异已被明确证明存在。众所周知，与居住在西方国家的高加索人群相比，亚洲人群中酪氨酸激酶结构域的突变更频繁。这些突变提供了更好的整体预后，并预测了对酪氨酸激酶抑制剂erlotinib和gefitinib的反应；然而，关于这些突变在美国占主导地位的少数族裔中的流行率的数据很少。在另一条重要的途径KRAS中，20%-30%的非小细胞肺癌患者存在突变。突变的KRAS与不良预后和对EGFR单抗西妥昔单抗以及EGFR酪氨酸激酶抑制剂erlotinib和gefitinib的耐药性有关。值得注意的是，KRAS和体细胞EGFR突变在非裔美国人中的流行率尚不清楚。最近，全基因组关联研究发现了尼古丁受体的单核苷酸多态(SNP)变异，该变异与非小细胞肺癌的遗传易感性增加有关。SNP变异频率的增加可能是导致非裔美国人非小细胞肺癌发病率增加的一个因素，但这些因素在该人群中的频率尚不确定。因此，需要努力更好地了解美国常见的种族和少数民族中疾病易感性、发病率、进展、预后和对生物制剂的反应的分子基础。综合梅哈里/范德比尔特-英格拉姆癌症中心研究伙伴关系进行研究，以解决代表不足的少数群体中不成比例的癌症发病率、发病率和死亡率。提出了一项双机构研究，以审查非裔美国人中记录的非小细胞肺癌病例，以确定胚系多态、体细胞EGFR突变和KRAS突变的频率。通过将已知肺癌患者与南方社区队列研究确定的年龄匹配的对照组进行比较，将确定非裔美国人尼古丁受体中的SNP的临床意义。被诊断为非小细胞肺癌的患者的医疗记录将被审查。基因测序将确定EGFR突变和KRAS突变的流行程度。这些突变的频率将作为独立变量进行分析，以确定与吸烟等已知风险因素比较时的临床意义。这项研究的目的是确定EGFR途径的扰动对患有非小细胞肺癌的非裔美国人的遗传易感性、疾病进展和预后的影响。这种性质的研究从未进行过。这一结果应该为影响非裔美国人非小细胞肺癌易感性、发病机制、药物敏感性和生存率的基因组因素提供巨大的洞察力。 公共卫生相关性：肺癌是美国癌症相关死亡的主要原因。大量研究表明，遗传性和获得性遗传损伤对肺癌的发病风险和靶向治疗的结果和疗效都有重要影响。这项研究的目的是确定EGFR途径的扰动对非裔美国人非小细胞肺癌的遗传易感性、疾病进展和预后的影响。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (09) Health Disparities and Specific Challenge Topic, 09-CA- 104: Basic cancer research in cancer health disparities. Title: Polymorphism and mutation spectrum in minorities with non-small cell lung cancer Lung cancer is the leading cause of cancer related deaths in the United States. Despite similar risk factors, African-Americans have higher incidence and mortality rates from lung cancer than other populations. Numerous studies have recently demonstrated that both inherited and acquired genetic lesions have a significant impact on both the risk of developing lung cancer and the outcomes and efficacy of targeted therapies. For example, the epidermal growth factor receptor (EGFR) signaling pathway is important in the development, progression, and invasion of non-small cell lung cancer. Ethnic differences in polymorphisms and acquired mutations in the EGFR and its downstream targets have been definitively proven to exist. It is well established that mutations in the tyrosine kinase domain are more frequent in Asian populations as compared to Caucasian population residing in western countries. These mutations confer better overall prognosis and predict response to the tyrosine kinase inhibitors, erlotinib and gefitinib; however, very little data is available regarding the prevalence of these mutations in the dominant U.S. racial minorities. In another important pathway, KRAS, mutations are present in 20-30% of patients with non-small cell lung cancer. Mutated KRAS is associated with poor prognosis and resistance to the monoclonal EGFR antibody, cetuximab as well as the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Notably, the prevalence of KRAS and somatic EGFR mutations in African-Americans is unknown. Recently, genome wide association studies identified a single nucleotide polymorphisms (SNP) variation in the nicotinic receptor which correlated with an increase in genetic susceptibility to non small cell lung cancer. Increased frequency of SNP variability may be one factor that contributes to the increased incidence of non-small cell lung cancer in African-Americans, but the frequency of these in this population is undefined. Thus efforts to better understand the molecular basis for disease susceptibility, incidence, progression, prognosis, and response to biologic agents among the common U.S. racial and ethnic minorities are needed. The Comprehensive Meharry/Vanderbilt-Ingram Cancer Center Research Partnership conducts research to address the disproportional cancer incidence, morbidity, and mortality in under-represented minorities. A dual institution study to review documented cases of non-small cell lung cancers in African-Americans to determine the frequency of germ line polymorphisms, somatic EGFR mutations, and KRAS mutations is proposed. The clinical significance of a SNP in the nicotinic receptor in African-Americans will be determined by comparing known lung cancer patients with age matched controls identified through the Southern Community Cohort Study. Medical records of patients diagnosed with non-small cell lung cancer will be reviewed. Gene sequencing will identify the prevalence of EGFR mutations and KRAS mutations. The frequency of these mutations will be analyzed as independent variables to determine the clinical significance when compared to known risk factors such as smoking. The goal of this study is to determine the impact of perturbations in the EGFR pathway on genetic susceptibility, disease progression, and outcome in African-Americans with nonsmall cell lung cancer. A study of this nature has never been performed. The results should provide tremendous insight into the genomic factors which influence susceptibility, pathogenesis, drug sensitivity, and survival in African-Americans with non-small cell lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer related deaths in the United States. Numerous studies have demonstrated that both inherited and acquired genetic lesions have a significant impact on both the risk of developing lung cancer and the outcomes and efficacy of targeted therapies. The goal of this study is to determine the impact of perturbations in the EGFR pathway on genetic susceptibility, disease progression, and outcome in African-Americans with non-small cell lung cancer.