Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant
Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant
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DOI：
10.1093/carcin/bgi248
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发表时间：
2006-03-01
期刊：
影响因子：
4.7
通讯作者：
Burwinkel, B
中科院分区：
文献类型：
--
作者：
Frank, B;Hemminki, K;Burwinkel, B
细胞凋亡的失调在肿瘤发生中起着至关重要的作用。作为死亡受体介导的细胞凋亡的一部分，同源物半胱天冬酶10和8可能作为低转移率乳腺癌（BC）易感基因。在死亡受体介导的细胞凋亡中，死亡受体与其配体的结合涉及死亡诱导信号复合物（DISC）的组装。在细胞色素介导的细胞凋亡中，细胞色素c释放到胞质溶胶中导致线粒体形成。半胱天冬酶10和8（分别为CASP 10和CASP 8）募集至DISC和溶酶体导致其通过二聚化活化。我们通过一项病例对照研究--使用511例家族性BC病例和547例对照受试者--研究了编码CASP 10变异V410 I（G1228 A）对BC风险的影响，并揭示了V410 I与降低风险的显著相关性。（OR = 0.62，95%CI = 0.43-0.88，P = 0.0076）与变异等位基因数相关（P趋势= 0.0039）。由于CASP 10和CASP 8在细胞凋亡过程中功能性合作，我们分析了CASP 10 V410 I和CASP 8 D302 H两者的相互作用，导致变异等位基因I410和H302的数量与家族性BC风险的高度降低之间存在显著关联。（OR = 0.35，P-trend = 0.007），提示CASP 10和CASP 8多态性在乳腺癌发生中存在交互作用。
Dysregulation of apoptosis plays a crucial role in carcinogenesis. As part of death receptor- and mitochondrion-mediated apoptosis, the homologues caspases 10 and 8 may act as low-penetrance breast cancer (BC) susceptibility genes. In death receptor-mediated apoptosis, engagement of death receptors by their ligands involves the assembly of the death-inducing signalling complex (DISC). In mitochondrion-mediated apoptosis, the release of cytochrome c into the cytosol results in apoptosome formation. Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization. We investigated the influence of the coding CASP10 variant V410I (G1228A) by performing a case-control study - using 511 familial BC cases and 547 control subjects - on BC risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43-0.88, P = 0.0076) related to the number of variant alleles (P-trend = 0.0039). As CASP10 and CASP8 functionally co-operate during apoptosis, we analysed the mutual effect of both CASP10 V410I and CASP8 D302H, resulting in a significant association between the number of the variant alleles I410 and H302 and a highly decreased familial BC risk (OR = 0.35, P-trend = 0.007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis.