Abstract
Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04–5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55–12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78–3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42–3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17–1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.
Highlights
Receptor activator of NF-kB (RANK) and RANKligand (RANKL) are key regulators of bone remodeling by controlling the activity of osteoclasts [1, 2]
single nucleotide polymorphisms (SNPs) rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS), and overall survival (OS)
In this study we show that from five selected RANK missense SNPs, SNP rs34945627 is more common in women with metastatic breast cancer (BC) when compared to healthy women
Summary
Receptor activator of NF-kB (RANK) and RANKligand (RANKL) are key regulators of bone remodeling by controlling the activity of osteoclasts [1, 2]. In human BC, RANK expression is mostly observed in hormone receptor-negative patients, being associated with higher proliferation index and histologic grade. It is associated with a poor clinical outcome, including a higher incidence of bone metastases (BM) [6, 7]. RANK-RANKL pathway inhibition is emerging as a clinically relevant therapeutic approach to prevent BC relapse, bone relapse [8]. The pathologic relevance of genetic polymorphisms within RANK-RANKL pathway has been previously reported, in particular for conditions affecting bone physiology. Several studies have described single nucleotide polymorphisms (SNPs) in osteoprotegerin (OPG), RANK or RANKL, which influence bone mineral density (BMD), or are associated with susceptibility to rheumatoid arthritis, peri-implantitis, and sporadic primary hyperparathyroidism-related lower BMD [9,10,11,12,13,14,15]
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