Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant

Carcinogenesis. 2006 Mar;27(3):606-9. doi: 10.1093/carcin/bgi248. Epub 2005 Oct 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Caspase 10
  • Caspase 8
  • Caspases / genetics*
  • Caspases / metabolism
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease*
  • Humans
  • Middle Aged
  • Mitochondria / physiology
  • Pedigree
  • Polymorphism, Genetic


  • CASP8 protein, human
  • Caspase 10
  • Caspase 8
  • Caspases
  • CASP10 protein, human