Polymorphisms in the RANK/RANKL genes and their effect on bone specific prognosis in breast cancer patients

Abstract

The receptor activator of NF-B (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

“…However, different reports have also suggested that low levels of RANK and RANKL expression in the breast cancer tissue confer a poorer prognosis (42). In fact, the interaction of the RANKL/RANK pathway with regards to the bone-related outcome of patients breast cancer appears complex, and certain nucleotide polymorphisms in RANK and RANKL genes have been associated with a poorer bone metastasis-free survival (43).…”

Tri̇ple-Negati̇f Meme Kanseri̇ Hastalarinda Rank, Rankl Ve Opg Genleri̇ndeki̇ Poli̇morfi̇zmleri̇n Beli̇rlenmesi̇ Ve Kemi̇k Metastazi Üzeri̇ne Etki̇si̇ni̇n İncelenmesi̇

“…In our study, no significant correlation was determined between all three groups with regard to RANK genotype and allele distributions (p>0.05). Hein et al reported no correlation between the prognosis of bone metastasis and RANK rs35211496 C/T polymorphism in breast cancer (23). It was concluded in the study of Santini et al on patients with breast cancer that RANK led to the development of bone metastasis in breast cancer (24).…”

Association of RANK and RANKL gene polymorphism with survival and calcium levels in multiple myeloma

“…The C variant was associated with susceptibility to Paget's disease of bone and knee osteoarthritis; conversely, it was found to have a protective role in hip osteoporotic fractures 26–28 . rs1805034 C was also a risk factor in esophageal cancer, but was not associated with risk for breast cancer 22,29,30 . These associations suggests that while the C allele seems to the causal variant, specific effects of the presence of the resultant valine‐including RANK protein may be different in various diseases.…”

“…We also checked for an association between RANKL and RANK SNPs, and serum concentration of the proapoptotic factor VEGF in a smaller group of patients (n = 32 [26][27][28] rs1805034 C was also a risk factor in esophageal cancer, but was not associated with risk for breast cancer. 22,29,30 These associations suggests that while the C allele seems to the causal variant, specific effects of the presence of the resultant valine-including RANK protein may be different in various diseases. rs1805034 C was also notably associated with age at menarche and postmenopausal osteoporosis in women, suggesting a female-specific effect.…”