Evolutionary analysis of CTCF and potential links to breast cancer phenotypes

描述（由申请人提供）：在美国人群中，不同种族的乳腺癌生存率存在显著差异，非洲裔美国女性的5年生存率明显低于欧洲裔美国女性。种族差异可以部分解释为风险因素暴露和获得医疗保健的差异，但在调整社会经济和环境因素后仍然存在显着差异[2-5]。AA女性的一些剩余风险增加可能归因于遗传背景，AA女性中与侵袭性肿瘤行为相关的等位基因频率较高。在乳腺癌中，一个经常失去杂合性的区域是染色体16q22 [6]， CTCF多功能转录因子位于其中，CTCF在乳腺癌细胞中的表达与对凋亡[7]的抵抗有关。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相一致，而该区域在非洲裔美国人bbb中具有正常的序列多样性。我们建议通过在一小组个体中对整个区域进行重测序来确定潜在的功能序列变异，然后评估在CARE研究中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.