A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936.
For Caucasians, CASP8-652 6N del was associated with reduced breast cancer risk at a borderline level (homozygous: OR=0.94, 95% CI 0.86-1.02, heterozygous: OR=0.96, 95% CI 0.90-1.03, recessive: OR=0.96, 95% CI 0.90-1.03, dominant: OR=0.94, 95% CI 0.88-1.01).
Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively.
In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8].
We found evidence of an association with breast cancer for CASP8D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.
Our results support that the presence of the CASP8D302H polymorphism diminishes the high risk of BC conferred by BRCA1 and BRCA2 mutations, making possible that some of the carriers could escape from suffering BC along their life span.
We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p = 0.0131).
Ten SNPs (rs2075555 in COL1A1, rs12652447 in FBXL17, rs10941679 in 5p12/MRPS30, rs11878583 in ZNF577, rs7166081 in SMAD3, rs16917302 in ZNF365, rs311499 in 20q13.3, rs1045485 in CASP8, rs12964873 in CDH1 and rs8170 in 19p13.1) were here genotyped in 1009 Chinese females (487 patients with breast cancer and 522 control subjects) using the Sequenom MassARRAY iPLEX platform.
Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the -652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population.
To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC).
To define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk.
Further subgroup analysis indicated that CASP8 -652 6N del polymorphism was associated with breast cancer, lung and gastrointestinal cancer susceptibility.
As CASP10 and CASP8 functionally co-operate during apoptosis, we analysed the mutual effect of both CASP10 V410I and CASP8D302H, 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.
Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05).
In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP).
AMR-Me induced DNA fragmentation and PARP degradation which were preceded by changing Bax/Bcl-2 ratios, cytochrome c release, and subsequent induction of pro-caspase-9 and -7 processing in breast carcinoma MCF-7 cells, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8, suggesting AMR-Me triggered the mitochondrial apoptotic pathway.