A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP |
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| Authors: | Harlid Sophia Ivarsson Malin I L Butt Salma Hussain Shehnaz Grzybowska Ewa Eyfjörd Jorunn Erla Lenner Per Försti Asta Hemminki Kari Manjer Jonas Dillner Joakim Carlson Joyce |
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| Institution: | 1. Department of Medical Microbiology, Lund University, Malm?, Sweden;2. Department of Clinical Chemistry, Lund University, Malm?, Sweden;3. RSKC Malm?, Wallenberg Laboratory, Malm?, Sweden;4. Department of Surgery, Lund University, Malm?, Sweden;5. Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA;6. Department of Molecular Biology, Centre of Oncology, Maria Sklodowska‐Curie Institute Gliwice, Poland;7. Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland;8. Department of Oncology, Norrlands University Hospital, Ume?, Sweden;9. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany;10. Center for Primary Care Research, Lund University, Malm?, Sweden;11. Departments of Laboratory Medicine, Medical Epidemiology and Biostatistics, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden;12. Labmedicin Sk?ne, Clinical Chemistry in Lund, SwedenFax: 046‐189114 |
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| Abstract: | Altered DNA methylation is often seen in malignant cells, potentially contributing to carcinogenesis by suppressing gene expression. We hypothesized that heritable methylation potential might be a risk factor for breast cancer and evaluated possible association with breast cancer for single nucleotide polymorphisms (SNPs) either involving CpG sequences in extended 5'-regulatory regions of candidate genes (ESR1, ESR2, PGR, and SHBG) or CpG and missense coding SNPs in genes involved in methylation (MBD1, MECP2, DNMT1, MGMT, MTHFR, MTR, MTRR, MTHFD1, MTHFD2, BHMT, DCTD, and SLC19A1). Genome-wide searches for genetic risk factors for breast cancers have in general not investigated these SNPs, because of low minor allele frequency or weak haplotype associations. Genotyping was performed using Mass spectrometry-Maldi-Tof in a screening panel of 538 cases and 1,067 controls. Potential association to breast cancer was identified for 15 SNPs and one of these SNPs (rs7766585 in ESR1) was found to associate strongly with breast cancer, OR 1.30 (95% CI 1.17-1.45; p-value 2.1 × 10(-6)), when tested in a verification panel consisting of 3,211 unique breast cancer cases and 4,223 unique controls from five European biobank cohorts. In conclusion, a candidate gene search strategy focusing on methylation-related SNPs did identify a SNP that associated with breast cancer at high significance. |
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| Keywords: | breast cancer methylation CpG SNPs ESR1 |
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