Circadian Genes and Aggressive Prostate Cancer in Caucasians and African American

描述(申请人提供)：非洲裔美国人的前列腺癌发病率和死亡率是世界上最高的，死于前列腺癌的可能性是高加索人的两倍多。造成这种种族差异的原因尚不清楚。最近，国际癌症研究机构(IARC)根据流行病学数据将昼夜节律紊乱归类为癌症的可能原因，该数据表明，涉及昼夜节律紊乱的轮班工作可能与更高的癌症风险相关，包括前列腺癌。在人体内，昼夜节律由15个已知的昼夜节律相关基因控制。这些基因的变异已被证明会影响雄激素代谢和能量平衡，这被认为是导致前列腺癌发生的原因。研究还表明，其中一种昼夜节律基因的单倍型模式在非洲人和非非洲人之间存在显著差异。我们假设，在高加索人和非裔美国人中，昼夜节律基因的变异都会影响前列腺癌的风险，特别是侵袭性前列腺癌，并且昼夜节律基因变异与侵袭性前列腺癌风险之间的关系可能在这两个种族之间有所不同，从而导致这两个群体中侵袭性前列腺癌的差异。为了验证这些假设，我们正在与非裔美国人前列腺癌基因联盟(AAPC)和乳腺癌和前列腺癌队列联盟(BPC3)合作，使用这两个联盟研究(4000例侵袭性前列腺癌病例和9500例对照)现有的遗传数据(来自15个基因的2700个单核苷酸多态)进行全面的统计分析。在这项研究的13,500名受试者中，约1,200名病例和5,000名健康对照是来自AAPC研究的非裔美国男性，2,800名病例和4,500名健康对照是来自BPC3研究的高加索男性。我们计划进行统计分析，以：1)确定昼夜节律基因变异是否与高加索人和非裔美国人患侵袭性前列腺癌的风险有关；2)确定昼夜节律基因变异与前列腺癌风险之间的关联在高加索人和非裔美国人中是否不同，以及这种差异是否解释了前列腺癌风险的部分种族差异。这是第一次有大量侵袭性前列腺癌病例的研究，特别是来自非裔美国人的病例，具有广泛的生理基因的SNP覆盖。因此，这项研究能够深入了解昼夜节律基因在前列腺癌中的作用，以及这些基因是否导致高加索人和非裔美国人前列腺癌发病率的种族差异。

DESCRIPTION (provided by applicant): African Americans have the highest incidence and mortality rates for prostate cancer in the world and are more than twice as likely to die of prostate cancer as their Caucasian counterparts. Reasons for this racial disparity are unknown. Recently, the International Agency for Research on Cancer (IARC) classified circadian rhythm disruption as a probable cause of cancer based on epidemiologic data suggesting that shift work involving circadian disruptions may be associated with higher risk of cancers, including that of the prostate. Within the body, circadian rhythms are controlled by 15 known circadian-related genes. Variations in these genes have been shown to influence androgen metabolism and energy balance, which are thought to contribute to the development of prostate cancer. It has also been shown that haplotype patterns in one of the circadian genes differ significantly between Africans and non-Africans. We hypothesize that variation in circadian genes affects the risk of prostate cancer, in particular aggressive prostate cancer, in both Caucasians and African Americans, and that the relationship between circadian gene variants and aggressive prostate cancer risk may differ between the two ethnic groups, thereby contributing to the disparity of aggressive prostate cancer in these two groups. To test these hypotheses, we are collaborating with the African American Prostate Cancer (AAPC) Genetic Consortium and the Breast and Prostate Cancer Cohort Consortium (BPC3) in using existing genetic data (2,700 single nucleotide polymorphisms from 15 genes) from these two consortium studies (4,000 aggressive prostate cancer cases and 9,500 controls) for a comprehensive statistical analysis. Of the 13,500 subjects included in the study, about 1,200 cases and 5,000 healthy controls are African American men from the AAPC study and 2,800 cases and 4,500 healthy controls are Caucasian men from the BPC3 study. We plan to conduct statistical analyses to: 1) determine if variation in circadian genes are associated with risk of aggressive prostate cancer in Caucasians and African Americans; and 2) determine whether the association between circadian gene variants and prostate cancer risk differs between Caucasians and African Americans and whether this difference explains part of the racial disparity in prostate cancer risk. This is the first study t have a large number of aggressive prostate cancer cases, especially from African Americans, with extensive SNP coverage of circadian genes. This study is therefore able to provide insight into the role of circadian genes in prostate cancer and whether these genes contribute to the racial disparity of prostate cancer rates between Caucasians and African Americans.