MacPherson Gordon, Healey Catherine S, Teare M Dawn, Balasubramanian Sabapathy P, Reed Malcolm W R, Pharoah Paul D P, Ponder Bruce A J, Meuth Mark, Bhattacharyya Nitai P, Cox Angela
Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK.
J Natl Cancer Inst. 2004 Dec 15;96(24):1866-9. doi: 10.1093/jnci/dji001.
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.
细胞凋亡，即程序性细胞死亡，在许多癌症中都会受到干扰。我们检验了以下假设：死亡受体4（DR4）、半胱天冬酶-8（CASP8）和半胱天冬酶-10（CASP10）基因的编码多态性可能作为低外显率的乳腺癌基因。在来自英国谢菲尔德的999例乳腺癌病例患者和996例对照受试者中，以及在来自东安格利亚的2192例病例患者和2262例对照受试者这一第二个独立的英国人群中，对这些基因的单核苷酸多态性（SNP）进行了基因分型。在谢菲尔德的研究中，CASP8的罕见H等位基因D302H与乳腺癌风险降低呈剂量依赖性相关（P趋势 = 0.007）。此外，CASP8 D302H的相关性在东安格利亚研究中得到了重复，但其他检测的CASP8 SNP（T21914C、G50121A和G50358A）则没有。乳腺癌的合并调整优势比，DH杂合子为0.83（95%置信区间[CI] = 0.74至0.94），HH纯合子为0.58（95%CI = 0.39至0.88）（P趋势 = 0.0002，经研究调整）。CASP8 D302H与乳腺癌之间可重复的、剂量依赖性的关联表明，细胞凋亡途径中的遗传变异在乳腺癌易感性中具有潜在重要性。
