title: A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP.
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.
authors.affiliation: Department of Medical Microbiology, Lund University, Malmö, Sweden.
authors.forename: Sophia
authors.initials: S
authors.lastname: Harlid
authors.forename: Malin I L
authors.initials: MI
authors.lastname: Ivarsson
authors.forename: Salma
authors.initials: S
authors.lastname: Butt
authors.forename: Shehnaz
authors.initials: S
authors.lastname: Hussain
authors.forename: Ewa
authors.initials: E
authors.lastname: Grzybowska
authors.forename: Jorunn Erla
authors.initials: JE
authors.lastname: Eyfjörd
authors.forename: Per
authors.initials: P
authors.lastname: Lenner
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Jonas
authors.initials: J
authors.lastname: Manjer
authors.forename: Joakim
authors.initials: J
authors.lastname: Dillner
authors.forename: Joyce
authors.initials: J
authors.lastname: Carlson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011980:Receptors, Progesterone / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone