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Carcinogenesis Advance Access published online on October 26, 2005
Carcinogenesis, doi:10.1093/carcin/bgi248
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 24, 2005
Revised September 20, 2005
Accepted October 18, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Bernd Frank 1*, Kari Hemminki 2, Barbara Wappenschmidt 3, Alfons Meindl 4, Rüdiger Klaes 5, Rita K. Schmutzler 3, Peter Bugert 6, Michael Untch 7, Claus R. Bartram 5, and Barbara Burwinkel 1

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany; Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden
3 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Germany; Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Germany
4 Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany
5 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
6 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessia, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany
7 Department of Gynaecology and Obstetrics at the Ludwig-Maximilians-University, Munich, Germany

* To whom correspondence should be addressed.
Bernd Frank, E-mail: b.frank{at}dkfz.de


  Abstract

Dysregulation of apoptosis plays a crucial role in carcinogenesis. As part of death receptor- and mitochondrion-mediated apotosis, the homologues caspase-10 and caspase-8 may act as low-penetrance breast cancer susceptibility genes. In death receptor-mediated apotosis, 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 caspase-10 and-8 to DISC and apoptosome leads to their activation by dimerization. We investigated the influence of the coding caspase-10 (CASP10) variant V410I (G1228A) by performing a case-control study - using 511 familial breast cancer cases and 547 control subjects - on breast cancer risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43 to 0.88, P = .0076) related to the number of variant alleles (Ptrend = .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 breast cancer risk (OR = 0.35, Ptrend = .007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis.


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