Lack of replication for the association between HER2 I655V polymorphism and breast cancer risk: A systematic review and meta-analysis

Background: Multiple epidemiological studies have investigated rs1136201, a non-synonymous polymorphism of the human epidermal growth factor receptor-2 gene (HER2) resulting in the substitution of valine for isoleucine at codon 655 (Ile655Val) of the HER2 protein, as a risk factor for breast cancer. Methods: We searched multiple databases to identify genetic association studies investigating the effect of rs1136201 on breast cancer risk. For each study we calculated unadjusted odds ratios (ORs) with their variance under additive, dominant, recessive and allele-frequency genetic models. Summary ORs with their corresponding confidence interval (CI) were calculated using random effects models. Results: Based on the 33 case–control studies reporting data for the additive genetic model (20,461 cases/23,832 controls) we did not find evidence of an association between rs1136201 and breast cancer, OR = 1.05 (95% CI, 0.99–1.11), with significant between-study heterogeneity (pQ < 0.001; I2 = 49%). Smaller studies produced more extreme results compared to larger studies (p = 0.001). Studies in which genotyping was not blind to case–control status (p = 0.01), studies not reporting the use of genotyping quality control (p = 0.01), and studies using RFLP-based methods (p = 0.01) produced significant associations. Meta-regression results confirmed that there was a significant interaction between lack of quality control (p = 0.04) and lack of blinding (p = 0.04) and the genetic effect of rs1136201 on breast cancer risk. Conclusions: It is unlikely that HER2 rs1136201 is a risk factor for breast cancer. Laboratory artifacts, lack of genotyping quality control or blinding and publication bias appear to have influenced the results published to date and need to be addressed in the design of future studies.