Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients

Li Wang,Sarrah E Widatalla,Diva S Whalen,Amos M Sakwe,Josiah Ochieng

doi:10.1186/s12885-017-3502-3

Li Wang, Sarrah E Widatalla + Show 3 more

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https://doi.org/10.1186/s12885-017-3502-3

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Journal: BMC Cancer	Publication Date: Aug 2, 2017
Citations: 18	License type: open-access

Affiliation: Vanderbilt University, Meharry Medical College

Abstract

BackgroundBreast cancer (BC) patients with late-stage and/or rapidly growing tumors are prone to develop high serum calcium levels which have been shown to be associated with larger and aggressive breast tumors in post and premenopausal women respectively. Given the pivotal role of the calcium sensing receptor (CaSR) in calcium homeostasis, we evaluated whether polymorphisms of the CASR gene at rs1801725 and rs1801726 SNPs in exon 7, are associated with circulating calcium levels in African American and Caucasian control subjects and BC cases.MethodsIn this retrospective case-control study, we assessed the mean circulating calcium levels, the distribution of two inactivating CaSR SNPs at rs1801725 and rs1801726 in 199 cases and 384 age-matched controls, and used multivariable regression analysis to determine whether these SNPs are associated with circulating calcium in control subjects and BC cases.ResultsWe found that the mean circulating calcium levels in African American subjects were higher than those in Caucasian subjects (p < 0.001). As expected, the mean calcium levels were higher in BC cases compared to control subjects (p < 0.001), but the calcium levels in BC patients were independent of race. We also show that in BC cases and control subjects, the major alleles at rs1801725 (G/T, A986S) and at rs1801726 (C/G, Q1011E) were common among Caucasians and African Americans respectively. Compared to the wild type alleles, polymorphisms at the rs1801725 SNP were associated with higher calcium levels (p = 0.006) while those at rs1801726 were not. Using multivariable linear mixed-effects models and adjusting for age and race, we show that circulating calcium levels in BC cases were associated with tumor grade (p = 0.009), clinical stage (p = 0.003) and more importantly, with inactivating mutations of the CASR at the rs1801725 SNP (p = 0.038).ConclusionsThese data suggest that decreased sensitivity of the CaSR to calcium due to inactivating polymorphisms at rs1801725, may predispose up to 20% of BC cases to high circulating calcium-associated larger and/or aggressive breast tumors.

Highlights

Breast cancer (BC) patients with late-stage and/or rapidly growing tumors are prone to develop high serum calcium levels which have been shown to be associated with larger and aggressive breast tumors in post and premenopausal women respectively
The calcium sensing receptor (CaSR) is pivotal in calcium homeostasis, its contribution in the previously reported association of high calcium with larger or more aggressive breast tumors remain unclear. We investigated whether these CASR single nucleotide polymorphisms (SNP) are associated with higher circulating calcium levels in control versus BC Caucasian and African American women
For genome-wide association studies (GWAS) we focused on polymorphisms at codons 986 and 1011 in exon 7 of the CASR as these correspond to inactivating mutant CaSRs with decreased sensitivity to calcium

Summary

Introduction

Breast cancer (BC) patients with late-stage and/or rapidly growing tumors are prone to develop high serum calcium levels which have been shown to be associated with larger and aggressive breast tumors in post and premenopausal women respectively. Available evidence reveals that serum calcium levels are elevated in women with untreated BC [3], and that high serum calcium levels are associated with aggressive breast tumors among premenopausal and/or overweight women [4], and larger breast tumors among postmenopausal women [5] Whether these high calcium associated breast cancer outcomes are related to the functional status of the calcium sensing receptor (CaSR) [6] remains unclear. The CaSR proteins with loss-of-function or inactivating mutations in the coding sequence have been shown to be less sensitive to calcium [17, 18] and linked with familial hypocalciuric hypercalcemia, more severe primary hyperparathyroidism, and the risk of kidney stones [13, 15, 19,20,21]

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