Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):351-355; doi:10.1093/carcin/bgm290
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SNPs in ultraconserved elements and familial breast cancer risk
1 Helmholtz-University Group Molecular Epidemiology
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
3 Center for Family and Community Medicine, Karolinska Institute, 69120 Huddinge, Sweden
4 Institute of Human Genetics, University of Heidelberg, 69120 Heidelberg, Germany
5 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, 50931 Köln, Germany
6 Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931 Köln, Germany
7 Department of Gynaecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
8 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, University of Heidelberg, Medical Faculty of Mannheim, 68167 Mannheim, Germany
9 Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
10 Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany
11 Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, 40225 Düsseldorf, Germany
* To whom correspondence should be addressed. Tel: +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 single-nucleotide polymorphisms (SNPs) within UCEs have 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 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] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06–1.30, P = 0.0020; [GG] versus [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] versus [A]: OR = 1.27, 95% CI 1.11–1.45, P = 0.0005; [GG] versus [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.
Abbreviations: BC, breast cancer; CI, confidence interval; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; SNP, single-nucleotide polymorphism; UCE, ultraconserved element
Received October 10, 2007; revised December 6, 2007; accepted December 10, 2007.