Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant.
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.
Frank
Bernd
B
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. b.frank@dkfz.de
Hemminki
Kari
K
Wappenschmidt
Barbara
B
Meindl
Alfons
A
Klaes
Rüdiger
R
Schmutzler
Rita K
RK
Bugert
Peter
P
Untch
Michael
M
Bartram
Claus R
CR
Burwinkel
Barbara
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology; D010375:Pedigree; D011110:Polymorphism, Genetic
C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human