Calcium-Sensing Receptor Polymorphisms at rs1801725 are Associated with Increased Risk of Secondary Malignancies

Abstract

AbstractPurposeDysregulation of systemic calcium homeostasis during malignancy is common in most patients with high grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry.MethodsMultivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms.ResultsCirculating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies.ConclusionsBreast, prostate, and skin cancer patients with homozygous inactivating variants (TT genotype) at the CASR rs1801725 locus have a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part, to cancer-induced hypercalcemia and/or tumor immune suppression.