Significant association of RANKL polymorphisms with bone metastasis among patients with breast cancer

The purpose of this study was to reveal the genetic correlation of RANKL polymorphisms with bone metastasis in breast cancer patients.

In this study, 139 bone metastasis patients and 152 no metastasis were included as the case and control groups. Real-time polymerase chain reaction (PCR) and allelic discrimination method were respectively applied for the genotyping of rs7325635 and rs2277438. Polymorphism genotype and allele frequencies were compared by χ² test between the two groups. The risk of bone metastasis development caused by RANKL genetic variants was evaluated by odds ratio (OR) with 95% confidence interval (95%CI). The linkage of two polymorphisms was examined by Haploview. Binary and multivariate logistic analyses were used to optimize the results.

Rs2277438 GG genotype and G allele frequencies were significantly higher in bone metastasis patients than that in no-metastasis patients (P < 0.05); they were significantly correlated with the increased risk of bone metastasis occurrence (GG: OR = 2.065, 95%CI=1.104-3.863; G: OR = 1.486, 95%CI=1.068-2.068). Compared with the G-G haplotype, the A-A haplotype was found to significantly reduce the risk of bone metastasis in breast cancer patients (OR = 0.647, 95%CI=0.436-0.959). The multivariate logistic analysis indicated that family history, Ki67, and rs2277438 were positively correlated with bone metastasis, but menopausal state, clinical staging, and rs7325635 were negatively correlated with bone metastasis in breast cancer.

The RANKL rs2277438 variant may be a potential genetic susceptibility factor associated with bone metastasis risk in breast cancer patients, though further functional validation is warranted. Rs7325635 was not independently associated with bone metastasis. The linkage disequilibrium between these two polymorphisms and their combined haplotype effect may play a role in bone metastasis susceptibility.