Circadian Genes and Breast Cancer

描述（由申请人提供）： 新近的研究表明，昼夜节律基因通过调控肿瘤抑制基因、细胞周期基因以及编码半胱天冬酶和转录因子的基因的表达，参与细胞增殖和凋亡的调控。因此，由于分子时钟调节肿瘤发生中的许多生物学途径，可以想象，昼夜节律基因的突变可能导致这些过程和肿瘤发展的失调。在这个提议中，我们假设与这些昼夜节律基因相关的不良基因型可能会调节其蛋白质功能的生物节律，从而影响个体对人类癌症的易感性。我们的具体目标是：1）确定单核苷酸多态性（SNPs）与昼夜节律基因的潜在功能影响。SNP将从公共SNP数据库中收集，并通过不同的生物信息学工具进行筛选。将对改变氨基酸的SNP和位于外显子剪接位点的SNP进行关于功能影响的预测。2)确定这些基因的特定多态性在乳腺癌风险调节中的作用。我们的假设是，预测在昼夜节律基因中具有功能意义的SNPs可能是与乳腺癌风险相关的一组新的生物标志物。3)探讨昼夜节律基因与环境因素尤其是夜间光照的联合作用。光是所有环境线索中最强大的昼夜节律同步器。我们的假设是，夜间暴露于光照可能会扰乱昼夜节律，从而增加具有昼夜节律基因中假定的高风险基因型的个体患乳腺癌的风险。鉴于可以获得DNA样本和接触数据，就实际可行性而言，这一建议既节省时间又节省成本。

DESCRIPTION (provided by applicant): Emerging data have demonstrated that circadian genes are involved in regulating cell proliferation and apoptosis by controlling expression of tumor suppressor genes, cell cycle genes, as well as genes that encode the caspases and transcription factors. Therefore, as the molecular clockworks regulate many biological pathways in tumorigenesis, mutations in circadian genes could conceivably result in deregulation of these processes and tumour development. In this proposal, we hypothesize that adverse genotypes associated with these circadian genes may modulate their protein functions in biology rhythms, thereby influencing an individual's susceptibility to human cancer. Our specific aims are: 1) To identify single nucleotide polymorphisms (SNPs) with potential functional impact on circadian genes. SNPs will be collected from public SNP databases and screened by different bioinformatic tools. Prediction about functional impact will be made to both SNPs that alter an amino acid and SNPs located in the exonic splicing sites. 2) To determine the role that specific polymorphisms in these genes play in the modulation of breast cancer risk. Our hypothesis is that SNPs predicted to have functional significance in circadian genes may be a novel panel of biomarkers to be associated with breast cancer risk. 3) To investigate the joint-effect between circadian genes and environmental factors, especially night exposure to light. Light is the most powerful circadian synchronizer among all environmental cues. Our hypothesis is that exposure to light at night may disturb circadian rhythms and consequently increase the risk of breast cancer for individuals with the putative high-risk genotypes in circadian genes. Given the availability of DNA samples and exposure data, this proposal is both time and cost effective in terms of practical feasibility.