Limited evidence supported the association of HRAS1 polymorphism with breast cancer risk

Abstract

We read with great interest the recent meta-analysis by Zhang et al. [1], which investigated the association between HRAS1 rare alleles and breast cancer risk. This study was very important as it clarified the controversial results among previous individual studies. Their metaanalysis indicated that HRAS1 rare alleles could increased the risk of breast cancer (odds ratio (OR) = 2.03, 95% confidence interval (CI) = 1.34–3.10). However, several methodological issues should be addressed in the study. First, the authors did not evaluate Hardy–Weinberg equilibrium (HWE) in the controls of included studies. Many evidences have indicated that not in HWE might reflect the presence of genotyping errors, population stratification, and selection bias in the controls [2–4]. Therefore, we suggested that HWE in controls should be assessed before the meta-analysis was performed. Second, as reported by the authors, publication bias existed among all the individual studies included (Egger test, P = 0.02). Publication bias usually indicated that positive studies were more likely to be published than the negative ones. In addition, as the meta-analysis included only published studies, it would generate the false positive result [3, 4]. Third, we noted that the meta-analysis was based on the majority of studies with small sample size in breast cancer cases (n \ 200) except for two most recent studies with relative large sample size in cases (n C 200). The studies with small sample size usually overestimate the true association, comparing to those with large sample size; moreover a large study with either finding might reflect the true association as it had sufficient statistical power [5]. Therefore, we performed the further meta-analysis by sample size in cases, and to re-assess the association between HRAS1 rare alleles and breast cancer risk (Fig. 1). The results suggested that HRAS1 rare alleles were not associated with the risk of breast cancer among relative large sample size in cases (OR = 0.93, 95% CI = 0.77–1.13). In summary, the conclusion should be made with caution for the association of HRAS1 polymorphism with breast cancer risk. Further well-designed studies with large sample size are needed to investigate the association between HRAS1 polymorphism with breast cancer.