Determinants of genetic penetrance in identical twins with breast cancer

乳腺癌同卵双胞胎遗传外显率的决定因素

• 批准号: 9355136
• 负责人: THOMAS McCulloch MACK
• 金额: $ 47.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355136
• 关键词: Adolescence; Adolescent; Adult; Affect; Aftercare; Age; Behavior; Blood; Breast Cancer Genetics; Characteristics; Childhood; Communities; DNA; DNA Methylation; Development; Diagnosis; Diet; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Gene Expression; Genetic; Genetic Determinism; Genetic Identity; Genetic Predisposition to Disease; Genetic Risk; Genome; Genotype; Histology; Lead; Life Style; Measures; Medical; Methylation; Monozygotic twins; Mutation; Paired Comparison; Pattern; Penetrance; Population; Predisposition; Prevention; Provider; Reporting; Risk; Role; Salivary; Sampling; Sexual Development; Sister; Tumor Pathology; Twin Multiple Birth; Variant; Woman; case control; design; experience; genetic risk factor; high risk; lifetime risk; malignant breast neoplasm; member; non-genetic; receptor; reproductive; risk variant; social; tumor

Technical Abstract In any population, with the presence of more than 100 genetic determinants, most breast cancer cases are likely to carry one, yet community occurrence is dominated by non-genetic risk factors. Adult identical twin women are representative of the population of origin in both genetic and non-genetic factors. However, when one gets breast cancer, the lifetime risk to the co-twin is much higher than expected on the basis of risk to an ordinary sister. Even so, only about a quarter of such co-twins become affected, and those that are become diagnosed years later. Thus affected pairs, whether breast cancer discordant or concordant, differ in the level of penetrance, and since the genetic determinants carried by concordant cases are unlikely to differ from those in discordant cases, the difference between such affected pairs, given the same genetic determinants, also reflects a different level of penetrance. We propose to verify the identity of genetic determinants between discordant and concordant pairs (using the Illumina OncoArray 500K), and to document the existence and timing of exogenous determinants of higher penetrance. This will be within discordant pairs, between the members of concordant pairs differing in age at diagnosis, and between cases from discordant and concordant pairs with the same or similar genotype. We will use adult twins' documented ability to accurately recall childhood differences between themselves in behaviors, environmental exposures, and given currant emphasis on adolescence, the rate of development. We will also use the Illumina HM450K BeadArray to evaluate whether the reported global hypo-methylation of WBCs from cases is attributable to the high risk genotype, and whether it persists after successful treatment.

技术摘要 在任何人群中，存在100多个遗传决定因素，大多数乳腺癌 案件可能会携带一个，但社区的发生由非遗传风险因素主导。 成人相同的双胞胎妇女代表了遗传和 非遗传因素。但是，当一个人患乳腺癌时，二线终身风险是 基于普通姐妹的风险要高得多。即便如此，只有一个 这种联合蛋糕的四分之一受到影响，几年后被诊断出来的。因此 受影响的对，无论是不一致的还是一致的乳腺癌，在外渗的水平上有所不同， 由于一致性案例携带的遗传决定因素不太可能与 在不一致的情况下，这种受影响的对之间的差异给定相同的遗传 决定因素，也反映了不同水平的渗透率。我们建议验证 不一致和一致对之间的遗传决定因素（使用Illumina OncoArray 500K），并记录外源决定因素的存在和时机 较高的渗透率。这将在不一致的对之间，在一致的成员之间 对诊断时年龄的成对以及与不一致和一致对的病例之间的成对 相同或相似的基因型。我们将使用成人双胞胎的记录能力准确回忆 在行为，环境暴露和给予的行为，环境暴露和给予的童年差异 醋栗对青春期的强调，发展速度。我们还将使用Illumina HM450K Beadarray评估WBC报告的全球甲基化是否是从 病例归因于高风险基因型，以及成功治疗后是否持续存在。