Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm290
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SNPs in Ultraconserved Elements and Familial Breast Cancer Risk
1 Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3 Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden
4 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
5 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Köln, Germany
6 Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Köln, Germany
7 Department of Gynaecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
8 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, University of Heidelberg, Medical Faculty of Mannheim, Mannheim, Germany
9 Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
10 Institute of Human Genetics, University of Regensburg, Regensburg, Germany
11 Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, Düsseldorf, Germany
Corresponding author: Rongxi Yang, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany, Phone: +49-6221-421461; Fax: +49-6221-421464; Email: r.yang{at}dkfz.de
Ultraconserved elements (UCEs) are segments of > 200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under representation of SNPs within UCEs has also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer. In the present study, we investigated the influence of six single nucleotide polymorphisms (SNPs) within UCEs on familial breast cancer risk. Two out of six SNPs showed an association with familial breast cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased familial breast cancer risk ([G] vs [A]: OR = 1.18, 95 % CI 1.06-1.30, P = 0.0020; [GG] vs [AA]: OR = 1.41, 95 % CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] vs [A]: OR = 1.27, 95 % CI 1.11-1.45, P = 0.0005; [GG] vs [AA]: OR = 1.60, 95 % CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with cancer risk.
Received October 10, 2007; revised December 6, 2007; accepted December 10, 2007.