Apoptosis can often be disrupted in cancer cells. Caspase-8 is an initiator caspase, which is part of the extrinsic apoptotic pathway. It has been shown that variants in CASP8 are involved in susceptibility to breast cancer. Recently, a four single nucleotide polymorphism (SNP) haplotype was found to increase breast cancer risk. The aim of this project was to fine-map the CASP8 gene region, in relation to breast cancer, by genotyping a panel of tagging SNPs in cases and controls, and by sequencing exons in haplotype carriers. Another aim was to test whether the 4-SNP haplotype, and two other CASP8 variants shown to be significantly involved in breast cancer susceptibility, might be responsible for the variations in risk via effects on the apoptotic response. The final aim was to carry out a replication study of CASP8 variants in prostate cancer. Fine-mapping of CASP8 was performed using DNA sequencing and multiplex genotyping. To test the apoptotic response; peripheral blood Iymphocytes from whole blood were induced into apoptosis and fluorescence activated cell sorting was used to measure levels of apoptosis and caspase-8 induction. The sequencing of all exons in CASP8 in 24 risk haplotype carriers and 23 protective haplotype carriers identified 22 variants in CASP8, 2 of which were novel. Fine- mapping of 1,015 breast cancer cases and 1,034 controls identified 6 SNPs significantly associated with breast cancer, two at p<O.OI. We found no association between genotype and caspase-8 activity or apoptosis. A replication study of seven CASP8 SNPs in 2,533 prostate cancer cases and 4,078 controls provided support for one SNP, p = 0.0004, but the evidence was less conclusive for the other six. These results support the hypothesis that variants in CASP8 are involved in breast and prostate cancer susceptibility, however further work is needed to identify the functional variants involved
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:574534 |
| Date | January 2011 |
| Creators | Parry, Marina |
| Publisher | University of Sheffield |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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