Association of a common variant of the CASP8 gene with reduced risk of breast cancer.
Apoptosis, or programmed cell death, is perturbed in many cancers. We tested the hypothesis that coding polymorphisms of the death receptor 4 (DR4), caspase-8 (CASP8), and caspase-10 (CASP10) genes might act as low-penetrance breast cancer genes. Single-nucleotide polymorphisms (SNPs) of these genes were genotyped in a series of 999 breast cancer case patients and 996 control subjects from Sheffield, U.K., and in a second, independent U.K. population of 2192 case patients and 2262 control subjects from East Anglia. In the Sheffield study, the rare H allele of CASP8, D302H, was associated with a reduced risk of breast cancer in a dose-dependent manner (P(trend) = .007). Furthermore, the CASP8 D302H association, but not that of the other CASP8 SNPs examined (T21914C, G50121A, and G50358A), was replicated in the East Anglian study. The combined adjusted odds ratios for breast cancer were 0.83 (95% confidence interval [CI] = 0.74 to 0.94) for the DH heterozygote and 0.58 (95% CI = 0.39 to 0.88) for the HH homozygote (P(trend) = .0002, adjusted for study). The reproducible, dose-dependent association of CASP8 D302H with breast cancer indicates the potential importance of inherited variation in the apoptosis pathway in breast cancer susceptibility.
MacPherson
Gordon
G
Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK.
Healey
Catherine S
CS
Teare
M Dawn
MD
Balasubramanian
Sabapathy P
SP
Reed
Malcolm W R
MW
Pharoah
Paul D P
PD
Ponder
Bruce A J
BA
Meuth
Mark
M
Bhattacharyya
Nitai P
NP
Cox
Angela
A
D001224:Aspartic Acid; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000235:genetics*; D004739:England; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006639:Histidine; D006720:Homozygote; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; D001224:Aspartic Acid; D006639:Histidine; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human