Purpose Multiple genome-wide and candidate-gene association studies have been conducted to search for common risk variants of breast cancer. Recent large meta-analyses and consolidating evidence have highlighted the role of the caspase-8 gene in breast cancer pathogenesis. Therefore, this study aimed to identify common variations and haplotypes associated with risk and overall survival of breast cancer with respect to underlying susceptibility variants in the CASP8 gene region in a group of the Iranian population. Methods In a case-control study with a total of 1008 samples (455 cases and 553 controls), genotyping of 12 candidate polymorphisms, consisting of rs3834129, rs2037815, rs7608692, rs12990906, rs3769821, rs6435074, rs3754934, rs3817578, rs10931936, rs1045485, rs1045487, and rs13113, were performed using PCR-based methods, including ARMSPCR, AS-PCR, RFLP-PCR, HRM-PCR, and TaqMan-PCR. Results rs3834129, rs3754934, rs12990906, and rs10931936 were associated with the risk and overall survival of breast cancer. Several haplotypes were also identified an associated with a higher risk of breast cancer, including a three-SNP haplotype rs3817578-rs10931936-rs1045485 [p<0.001, OR=1.78(1.32–2.41)]. rs3754934-C allele showed an association with a lower risk of death in all patients [p=0.022; HR=0.46(0.23–0.89)] and in the hormone-receptor-positive group [p=0.038; HR=0.37(0.14–0.95)], as well as CC genotype in the hormone-receptor-positive group [p=0.002; HR=0.09(0.02–0.43)]. Conclusion The present study suggests a diagnostic and prognostic role of CASP8 gene variations in breast cancer. The risky haplotypes are likely to have one or more underlying breast cancer susceptibility alleles. Understanding the mode of action of these alleles will aid individual-level risk prediction. It also may help identify at-risk patients to provide them with better surveillance.

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