GENETIC EPIDEMIOLOGY OF LUNG CANCER

肺癌的遗传流行病学

• 批准号: 2101444
• 负责人: Ann G. Schwartz
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-15 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101444
• 关键词: age difference; blood chemistry; cytochrome P450; environment related neoplasm /cancer; family genetics; gene expression; genotype; human genetic material tag; human middle age (35-64); human subject; interview; lung neoplasms; mathematical model; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nucleic acid sequence; passive smoking; pathologic process; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; tobacco abuse; tumor suppressor genes; young adult human (21-34)

Familial aggregation of lung cancer was first reported over 30 years ago. A recent genetic epidemiology study found that the pattern of lung cancer occurrance in families was consistent with Mendelian codominant inheritance of a rare autosomal gene with variable age at onset. In addition, evidence from genetic studies suggests that genetically- determined polymorphisms in the microsomal mixed-function oxidases (cytochrome P450s) affect risk of lung cancer. Tumor suppressor genes also have been identified which appear to play a role in familial cancers. Our goal is to evaluate the role of genes and the environment in the etiology of lung cancer, focusing on two risk groups expected to have risk associated with genetic susceptibility. These groups include non-smokers and persons under age 45 years at diagnosis. This population-based case-control study will include approximately 250 non- smoking lung cancer cases age 40-84 years, 250 non-smoking, non-cancer controls age 40-84 years, 400 lung cancer cases under 45 years of age selected without regard to smoking status and 400 non-cancer controls under 45 years of age. The cases are identified through the Metropolitan Detroit Cancer Surveillance System, a participant in NCI's SEER program. These cases and controls, or their proxies, will provide detailed questionnaire data, through a telephone interview, about environmental exposures for their parents, siblings, children and spouse (approximately 10,000 individuals in total). Tumor specimens for cases will be obtained, as will blood samples from controls, for genetic analyses. This study population, which is 29% black and 59% female, will be used to address the following specific aims: 1) to determine if there is heterogeneity of lung cancer risk among families after accounting for individually measured environmental risk factors; 2) to determine if the contribution to risk from familial factors and individual exposures varies by histologic type and race; 3) to determine if there is familial heterogeneity for risk of other cancers and other respiratory diseases; 4) to determine the contribution of genetic and environmental factors to the distribution of lung cancer, other cancers, and other respiratory diseases in families; 5) to evaluate differences in risk of lung cancer by genotype at the P450 loci, CYP1A1 and CYP2E1, in cases and controls; 6) to determine the frequency and type of mutations at the p53 tumor suppressor locus in the cases; and 7) to determine if a correlation exists between the frequency and nature of identified p53 mutations and P450 genotypes. The proposed project represents a logical progression in defining the contribution of genes and environment in risk of lung cancer. The interview component will provide us with data about individually measured environment risk factors which need to be accounted for when determining familial risk. Familial risk will be resolved into its components using segregation analysis to determine contributions from unmeasured, shared environments and from genetic inheritance. We look for specific genes that may be responsible for increased susceptibility and describe genetic changes at the tumor level. This is a powerful strategy, made even more powerful by the unique study populations and the large sample size.

肺癌的家族性聚集在30年前首次报道。 最近的一项遗传流行病学研究发现，肺癌的模式 家庭中的出现与门德利的共同指导一致 发作时年龄变化的稀有常染色体基因的遗传。 在 此外，遗传研究的证据表明，遗传学上 确定的微粒混合功能氧化酶中的多态性 （细胞色素P450）影响肺癌的风险。 肿瘤抑制基因 也已经确定了似乎在家族中起作用的 癌症。 我们的目标是评估基因和环境的作用 在肺癌的病因学中，重点是预期的两个风险群体 具有与遗传敏感性相关的风险。 这些组包括 诊断时的非吸烟者和45岁以下的人。 这 基于人群的病例对照研究将包括大约250个非 - 吸烟肺癌病例40-84岁，250个非吸烟，非癌症 控制年龄40-84岁，45岁以下的400例肺癌病例 无需考虑吸烟状况和400个非癌症控制 45岁以下。 这些案件是通过大都会确定的 NCI SEER计划的参与者底特律癌症监视系统。 这些案例和控件或其代理将提供详细的 问卷数据，通过电话采访，有关环境 为父母，兄弟姐妹，子女和配偶接触（大约 总共10,000个人）。 病例的肿瘤标本将是 从对照组中获得的血液样本也获得了遗传分析。 该研究人群将使用29％的黑色和59％的女性 解决以下具体目的：1）确定是否存在 核算后，家庭中肺癌风险的异质性 单独测量的环境风险因素； 2）确定是否 来自家族因素和个人暴露的风险的贡献 因组织学类型和种族而异； 3）确定是否有家族性 其他癌症和其他呼吸系统疾病的风险异质性； 4）确定遗传和环境因素的贡献 肺癌，其他癌症和其他呼吸道的分布 家庭疾病； 5）评估肺癌风险差异 在P450基因座，CYP1A1和CYP2E1的基因型中，在情况和对照中； 6）确定p53肿瘤处突变的频率和类型 在情况下抑制基因座； 7）确定是否相关 存在于已识别的p53突变的频率和性质之间 P450基因型。 拟议的项目代表了逻辑进步 定义基因和环境在肺风险中的贡献 癌症。 面试部分将为我们提供有关的数据 需要考虑的单独测量的环境风险因素 在确定家庭风险时。 家族风险将解决 其组件使用隔离分析来确定 未满足的共享环境和遗传遗传。 我们看 对于可能导致易感性提高的特定基因 并描述肿瘤水平的遗传变化。 这是一个强大的 策略，使独特的研究人群和 大型样本量。