A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers

Abstract

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor-induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose-dependent manner. These results support the hypothesis that genetic variants influencing immune status modify cancer susceptibility.

A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk

“…By means of the mRNA target gene prediction database (http://microrna.sanger.ac.uk/), we found more than 1,000 target genes of miR-27a, including some cancer-related genes, such as aspartate-specific cysteine protease (CASP8) [55], mutL homolog 1(MLH1), vascular endothelial growth factor C (VEGFC), and BCL2-associated X protein (BAX). Scott et al found that the transcription of ZBTB10 is upregulated after miR-27a antisense transfection [56].…”

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation

“…19 The decrease in caspase-8 activity was dependent on the number of deletions present (less activity in homozygotes compared to heterozygotes). In our study, the levels of luminescence were comparable among the three CASP8 genotypes (performed by comparing the level of relative luminescence units by using a homogenous luminescent assay consisting of thermostable luciferase, data not shown).…”

“…These primers have been previously described. 19 Single-round PCR amplification was performed using AmpliTaq Gold DNA polymerase (Applied Biosystems, Foster City, CA, USA). Each reaction consisted of 10x Taq buffer, 25 mM MgCl 2 , 1 μM of reverse primer, 1 μM of forward primer, 1 unit of AmpliTaq Gold, 150 μM dNTP mix and approximately 100 ng of subject DNA.…”

“…16 A six-nucleotide insertion/deletion variant (rs3834129, − 652 6Ndel AGTAAG) in the promoter of the CASP8 gene, which encodes the caspase-8 protein, has been associated with reduced susceptibility to multiple cancers, including non-Hodgkin's Lympoma, 17,18 and it has been shown that the polymorphism has an effect on the susceptibility of T lymphocytes to undergo apoptosis. 19 This is due to the destruction of a binding site for the transcriptional activator SP1 and a consequent decrease in caspase-8 transcription. T lymphocytes from CASP8 − 652 6Ndel homozygous (del/del) and heterozygous wild-type (WT) and del-(WT/del) individuals showed reduced AICD rates upon stimulation with cancer cell Ags and resistance to apoptosis in an allele dose-dependent manner.…”

“…T lymphocytes from CASP8 − 652 6Ndel homozygous (del/del) and heterozygous wild-type (WT) and del-(WT/del) individuals showed reduced AICD rates upon stimulation with cancer cell Ags and resistance to apoptosis in an allele dose-dependent manner. 19 The conclusions drawn from these studies were that homozygotes for the − 652 6Ndel polymorphism are less susceptible to the development of cancer because of reduced AICD of T lymphocytes.…”