Determinants of genetic penetrance in identical twins with breast cancer

技术摘要 在任何存在100多个基因决定因素的人群中，大多数乳腺癌 病例很可能携带一种，然而社区发生是由非遗传风险因素主导的。 成年同卵双胞胎女性在基因和基因上都代表了起源的人群。 非遗传因素。然而，当其中一人患上乳腺癌时，同卵双胞胎的终生风险是 在对一个普通姐妹的风险基础上，远远高于预期。即便如此，也只有大约一个 这些同卵双胞胎中有四分之一会受到影响，而那些在几年后被诊断出来的人会受到影响。因此， 受影响的配对，无论是不和谐的乳腺癌还是和谐的乳腺癌，在外显水平上都不同， 由于符合的病例携带的基因决定因素不太可能与 在不一致的情况下，由于相同的基因，这些受影响的对之间的差异 决定因素，也反映了不同水平的外显。我们建议核实 不协调对和协调对之间的遗传决定因素(使用Illumina OncoArray 500K)，并证明外源决定因素的存在和时机 更高的清晰度。这将在Concordant的成员之间的不和谐的对内 诊断时年龄不同的配对，以及不一致和一致的配对 相同或相似的基因。我们将使用成年双胞胎的记录能力来准确地回忆 童年时期他们之间在行为、环境暴露和给予方面的差异 目前强调的是青春期的发育速度。我们还将使用光明灯 HM450K珠状阵列评估报告的WBC全球低甲基化是否来自 这些病例与高危基因有关，以及在成功治疗后是否持续存在。

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.