Journal Article

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

Bernd Frank, Kari Hemminki, Barbara Wappenschmidt, Alfons Meindl, Rüdiger Klaes, Rita K. Schmutzler, Peter Bugert, Michael Untch, Claus R. Bartram and Barbara Burwinkel

in Carcinogenesis

Volume 27, issue 3, pages 606-609
Published in print March 2006 | ISSN: 0143-3334
Published online October 2005 | e-ISSN: 1460-2180 | DOI:
Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant

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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 (Ptrend = 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, Ptrend = 0.007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis.

Keywords: BC, breast cancer; CASP8, caspase 8; CASP10, caspase 10; CFLAR, CASP8 and FADD-like apoptosis regulator; 95% CI, 95% confidence interval; DED, death effector domain; DISC, death-inducing signalling complex; FADD, Fas-associating protein with death domain; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism; TNF, tumour necrosis factor

Journal Article.  2652 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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