Evolutionary analysis of CTCF and potential links to breast cancer phenotypes

描述(由申请人提供)：在美国人口中，不同种族之间的乳腺癌存活率存在显著差异，与欧洲裔美国女性相比，非洲裔美国女性的五年存活率显著较低[1]。族裔差异可以部分解释为风险因素暴露和获得保健的机会的差异，但在对社会经济和环境因素进行调整后，仍然存在显著的差异[2-5]。再生障碍性贫血妇女的部分残余风险增加可能归因于遗传背景，再生障碍性贫血妇女与侵袭性肿瘤行为相关的等位基因频率较高。在乳腺癌中经常发生杂合性缺失的一个区域是染色体16q22[6]，CTCF多功能转录因子位于该区域，而CTCF在乳腺癌细胞中的表达与对细胞凋亡的抵抗有关[7]。我们最近证明，CTCF两侧的区域在欧亚人中具有异常低的序列多样性，这与近代史上对该区域的强烈选择压力一致，而该区域在非裔美国人中显示出正常的序列多样性[8]。我们建议通过对一小群个体中的整个区域进行重新测序来识别潜在的功能序列变异，然后在CARE研究中评估假定的功能变异是否可能与非裔美国人乳腺癌病例的分期和激素受体状态有关。

DESCRIPTION (provided by applicant): In the US population, substantial differences exist between ethnicities in breast cancer survival, with a significantly lower five year survival rate in African American women, as compared to European American women[1]. The ethnic disparity can be partially explained by differences in risk factor exposure and access to health care, but a significant disparity remains after adjusting for socio-economic and environmental factors [2-5]. Some of the residual increased risk for AA women might be attributable to genetic background, with higher allele frequencies in AA women for alleles associated with aggressive tumor behavior. One region with frequent loss of heterozygosity in breast cancer is chromosome 16q22 [6], within which the CTCF multifunctional transcription factor lies, and CTCF expression in breast cancer cells has been associated with resistance to apopotosis [7]. We recently demonstrated that the region flanking CTCF has unusually low sequence diversity in Eurasians, consistent with strong selective pressure on this region in recent history, whereas the region shows normal sequence diversity in African Americans [8]. We propose to identify potentially functional sequence variation by resequencing the entire region in a small panel of individuals, and then to assess whether putatively functional variation might be related to stage and hormone receptor status of African American breast cancer cases in the CARE study.