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. 2021 Jul 6;11(7):642.
doi: 10.3390/jpm11070642.

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

Ky'Era V Actkins  1 , Heather K Beasley  2 , Annika B Faucon  3 , Lea K Davis  2   4 , Amos M Sakwe  2
Affiliations

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

Ky'Era V Actkins et al. J Pers Med. .

Abstract

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.

Keywords: A986S; calcium-sensing receptor; cancer-induced hypercalcemia; electronic health records; metastasis; phenome-wide association study; rs1801725.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Association of circulating calcium, parathyroid hormone, and vitamin D levels with cancer risk. Forest plots showing the odds associated with circulating levels of the indicated laboratory values and diagnosis of cancer at the indicated pathologic sites. The dashed line in each plot represents an odds ratio (OR) of 1. PTH = intact parathyroid hormone, VITD = vitamin D, IONCAL = ionized calcium.
Figure 2
Figure 2
Circulating total calcium and ionized calcium in CaSR rs1801725 allele carriers. Top row (a,b): European dataset; bottom row (c,d): African dataset. The Wilcoxon rank sum test was used to compare the median circulating total (a) and ionized (b) calcium levels in individuals of European descent, and total (c) and ionized (d) calcium levels in individuals of African descent expressing the indicated polymorphisms at rs1801725 depicted by the genotype. p < 0.05 was considered statistically significant.
Figure 3
Figure 3
Association of circulating calcium levels with secondary cancer phenotypes. Logistic regression models were performed on secondary cancer and the CASR variants at rs1801725. The additive (red) and recessive (green) models were adjusted for median age, sex, and the first ten principal components. * indicates p < 0.01 in the logistic regression model. OR = odds ratio.
See this image and copyright information in PMC

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