Evolutionary analysis of CTCF and potential links to breast cancer phenotypes

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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.