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[Cancer Research 66, 9420-9427, October 1, 2006]
© 2006 American Association for Cancer Research


Molecular Biology, Pathobiology, and Genetics

ERCC4 Associated with Breast Cancer Risk: A Two-Stage Case-Control Study Using High-throughput Genotyping

Roger Laughlin Milne1, Gloria Ribas2, Anna González-Neira1, Rainer Fagerholm4, Antonio Salas5, Emilio González1, Joaquín Dopazo6, Heli Nevanlinna4, Mercedes Robledo3 and Javier Benítez1,2

1 National Genotyping Centre, 2 Human Genetics Group, 3 Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain; 4 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland; 5 Unidad de Genética, Instituto de Medicina Legal, Facultad de Medicina, Universidad de Santiago de Compostela, Galicia, Spain; and 6 Department of Bioinformatics, Centro de Investigación Príncipe Felipe, Valencia, Spain

Requests for reprints: Javier Benítez Human Cancer Genetics Programme, Spanish National Cancer Centre, Melchor Fernández Almagro, 3 E-28029, Madrid, Spain. Phone: 34-91-224-6965; Fax: 34-91-224-6923; E-mail: jbenitez{at}cnio.es.

The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer. (Cancer Res 2006; 66(19): 9420-7)




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2006 by the American Association for Cancer Research.