title: A breast cancer risk haplotype in the caspase-8 gene.
abstract: Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
authors.affiliation: Institute for Cancer Studies, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Neil Duncan
authors.initials: ND
authors.lastname: Shephard
authors.forename: Ryan
authors.initials: R
authors.lastname: Abo
authors.forename: Sushila Harkisandas
authors.initials: SH
authors.lastname: Rigas
authors.forename: Bernd
authors.initials: B
authors.lastname: Frank
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Ian Wallace
authors.initials: IW
authors.lastname: Brock
authors.forename: Adam
authors.initials: A
authors.lastname: Shippen
authors.forename: Sabapathy Prakash
authors.initials: SP
authors.lastname: Balasubramanian
authors.forename: Malcolm Walter Ronald
authors.initials: MW
authors.lastname: Reed
authors.forename: Claus Rainer
authors.initials: CR
authors.lastname: Bartram
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Rita Katharina
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Lisa Anne
authors.initials: LA
authors.lastname: Cannon-Albright
authors.forename: Kristina
authors.initials: K
authors.lastname: Allen-Brady
authors.forename: Nicola Jane
authors.initials: NJ
authors.lastname: Camp
authors.forename: Angela
authors.initials: A
authors.lastname: Cox