The functional Role of CASP8 D302H and Other Apoptosis Gene Variants In Breast Cancer

Rigas, Sushila H.; Parry, Marina; Reed, Malcolm W. and Cox, Angela (2009). The functional Role of CASP8 D302H and Other Apoptosis Gene Variants In Breast Cancer. In: Journal of Medical Genetics, BMJ, 46 S108.


It is well established that perturbations in high penetrance genes such as BRCA1 and BRCA2 predispose to breast cancer. However, low penetrance genes are still under investigation. We recently reported that a coding single nucleotide polymorphism (SNP) in the caspase 8 gene (CASP8 D302H) is associated with a reduced risk of breast cancer. More recently we identified a CASP8 4-SNP haplotype associated with an increased risk of breast cancer. Our hypothesis is that CASP8 and other apoptotic genes influence breast cancer susceptibility via effects on the apoptotic response.

Our objectives are to study the functional effects of CASP8 D302H and the 4-SNP haplotype on apoptosis induction in peripheral blood lymphocytes (PBLs).

We have recruited women attending mammography screening and measured the ability of their PBLs to undergo drug-induced apoptosis. Levels of apoptosis and caspase-8 activity were determined by FACS analysis.

Based on data from 61 samples, apoptosis levels range from 50% to 92% (median 78%, SD 9.5) and CASP8 protein levels 44% to 94% (median 68%, SD 13.2). We have successfully detected variations in apoptotic/CASP8 response and aim to determine whether these variations correlate with CASP8 genotype, to help us understand the mechanism of the association with breast cancer.

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