Abstract 3928: Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients

Abstract

Abstract Patients with metastatic or end-stage breast cancer (BC) inevitably develop hypercalcemia, while up to 30% of BC patients develop cancer-induced hypercalcemia (CIH) in the absence of metastases or bone diseases. The commonly diagnosed mild increase in circulating calcium activates the calcium sensing receptor (CaSR) and has been shown to be associated with larger and more aggressive breast tumors in postmenopausal and premenopausal patients respectively. Whether differences in circulating calcium and/or specific inactivating CaSR variants play any role in disparities in BC outcomes remains unclear. DESIGN METHODS: We identified 199 BC cases and 384 age and genetic ancestry-matched controls with calcium assay and genotyping data from the Vanderbilt University DNA biorepository (BioVU) linked to de-identified electronic medical records. The linear mixed effects and codominant models were used to assess the relationship between inactivating CaSR mutations at rs1801725 (codon 986) and rs1801726 (codon 1011) and either circulating calcium levels or risk of high calcium-driven aggressive BC outcomes. RESULTS: We observed that circulating calcium levels were significantly higher in BC cases compared to control subjects (p=0.001) and interestingly, in subjects of African ancestry compared to Caucasians (p=0.001). The A986S mutant CaSR is common among Caucasians while the Q1011E mutant receptor is common among African Americans. However, only inactivating mutations at rs1801725 locus were significantly associated with higher calcium levels (p=0.006) and a higher (69%) risk of high calcium-driven aggressive BC outcomes compared to the wild type receptor. We also demonstrate that invasive BC cells are tolerant to sustained high calcium and that their adaptation to high calcium occurs via up-regulation of calcium-activated early response and malignancy-associated genes. CONCLUSION: These data suggest that inactivating CaSR polymorphisms at rs1801725 predispose BC patients to hypercalcemia and that high circulating calcium-driven aggressive disease outcomes occur via calcium modulated malignancy-associated genes such as MAGEC2/CT10. Citation Format: Diva Whalen, Li Wang, Sarrah Widatalla, Josiah Ochieng, Ann Richmond, Amos Sakwe. Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3928. doi:10.1158/1538-7445.AM2017-3928