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

Abstract

Multiple myeloma (MM) is a heterogeneous bone marrow cancer characterized by proliferation of malignant plasma cells in the bone marrow. One of its major symptoms are hypercalcaemia and bone lesions, which may result in pathologic bone fractures. Receptor activator for nuclear factor κB (RANK) and its ligand, RANKL, are part of an activation pathway for osteoclasts and are thus responsible for bone resorption. Furthermore, RANKL expression is increased in multiple myeloma. In the present study, we investigated the role of single nucleotide polymorphisms (SNPs) in the genes coding for RANK (rs1805034, rs8086340), RANKL (rs7325635, rs7988338), and TACI (rs34562254), a receptor for osteoclast-derived pro-survival factors. The study involved 222 patients and 222 healthy individuals, and the analysis included disease susceptibility, survival, bone lesions, calcium levels, and vascular endothelial growth factor levels. Patients with allele RANK rs1805034 C had higher survival (p = .003). This relationship was especially evident in women (p = .006). Furthermore, allele rs1805034 C was associated with slightly lower median age at diagnosis (64.0 vs. 65.5, p = .008). Allele RANKL rs7325635 A correlated with lower progression-free survival (p = .027), and with lack of early progression (p = .023). Additionally, women with allele rs7325635 G were found to have higher calcium blood concentration (p = .040). Allele TACI rs34562254 A was more common in MM patients in more advanced stages (II and III stage International Staging System) at diagnosis (p = .017), and the SNP showed a slight trend towards association in a multivariate analysis (p = .084). Taken together, our results suggest that RANK rs1805034 and RANKL rs7325635 may have a role in MM development and progression.

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

“…Another study reported that mast cell infiltration is inversely correlated with prognosis in patients with lung cancer ( Imada et al, 2000 ). Moreover, proliferation of malignant plasma cells in the bone marrow is a characteristic manifestation of multiple myeloma ( Łacina et al, 2020 ). Above all, the tumor-infiltrating immune cell environment indicates the immune status of patients with cancer, which may account for the difference in survival outcomes between the high-risk and low-risk groups.…”

Current perspectives on interethnic variability in multiple myeloma: Single cell technology, population pharmacogenetics and molecular signal transduction

“… Italian 137 MICA -129 Val/Val ( [56] -129 Val/Met -129 Met/Met 4. Polish 144 IRF4 CRBN rs872071 (G variant) rs711613 (A variant) [57] ) 54 CXCR4 CXCL12 rs2228014 rs1801157 [58] 135 BSG MCT1/SLC16A1 rs4919859 C rs8637 G rs7556664 A rs7169 T rs1049434 A ( [59] 132 bFGF rs308395 (G>C)/-921G [60] ) 222 RANK rs1805034 (C variant [61] ) RANKL rs7325635 (A and G variants TACI rs34562254 (A variant) 100 PSMA6 CG+GG genotypes [62] ) NOD2/CARD15 3020insC 5. Danish 348 IL1B C-3737T (wild type [63] ) 348 IL1B C-3737T (T variant [64] ) 296 NFKB1 -94ins/delATTG (wild type [65] ) 348 CD3EAP rs967591 (G-21A [66] ) RAI (intron 1-1 rs4572514 348 IL-1β T-31C …”

“…While the A variant of rs7325635 (RANKL SNP) showed lack of early myeloma progression and lower PFS, the G variant in women resulted in higher Ca +2 levels in blood. Interestingly, the A variant of rs34562254 (TACI SNP) was frequently seen in advanced cases at diagnosis [61] . While PSMA6 CG+GG genotypes had shorter OS, increased risk of progressive disease and higher risk of death, NOD2/CARD15 3020insC increased sensitivity to bortezomib along with a reduced risk of renal dysfunction in 100 newly diagnosed cases from Poland (ethnicity not known) [62] .…”

Modern markers for evaluating bone disease in multiple myeloma (Review)

“…The osteolytic bone disease results from an increased osteoclast activity and reduced osteoblast function, characteristic of myeloma. Bone loss in MM is multifactorial; during the disease most of the patients develop a severe osteolytic bone disease (6,7). It is still unclear why bone destruction is a common component of this disease.…”