Dysregulation 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. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating
calcium,
parathyroid hormone,
vitamin D, and primary and secondary
neoplasms. Circulating
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. Our data suggest that expression of CaSR variants at rs1801725 is associated with 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. Screening of patients for CASR variants at this locus may lead to improved management of high
calcium associated
tumor progression.