Wang Li, Widatalla Sarrah E, Whalen Diva S, Ochieng Josiah, Sakwe Amos M
Vanderbilt Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.
Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, 37208, USA.
BMC Cancer. 2017 Aug 2;17(1):511. doi: 10.1186/s12885-017-3502-3.
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. 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.
In 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.
We 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).
These 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.
患有晚期和/或快速生长肿瘤的乳腺癌（BC）患者容易出现血清钙水平升高，这已被证明分别与绝经后和绝经前女性中更大且侵袭性更强的乳腺肿瘤有关。鉴于钙敏感受体（CaSR）在钙稳态中的关键作用，我们评估了第7外显子中CASR基因的rs1801725和rs1801726单核苷酸多态性（SNP）是否与非裔美国人和白人对照受试者以及BC病例的循环钙水平相关。
在这项回顾性病例对照研究中，我们评估了199例病例和384例年龄匹配对照者的平均循环钙水平，以及rs1801725和rs1801726这两个失活性CaSR SNP的分布，并使用多变量回归分析来确定这些SNP是否与对照受试者和BC病例的循环钙相关。
我们发现非裔美国受试者的平均循环钙水平高于白人受试者（p < 0.001）。正如预期的那样，BC病例的平均钙水平高于对照受试者（p < 0.001），但BC患者的钙水平与种族无关。我们还表明，在BC病例和对照受试者中，rs1801725（G/T，A986S）和rs1801726（C/G，Q1011E）的主要等位基因分别在白人和非裔美国人中较为常见。与野生型等位基因相比，rs1801725 SNP处的多态性与较高的钙水平相关（p = 0.006），而rs1801726处的多态性则不然。使用多变量线性混合效应模型并对年龄和种族进行调整后，我们表明BC病例的循环钙水平与肿瘤分级（p = 0.009）、临床分期（p = 0.003）相关，更重要的是，与rs1801725 SNP处CASR的失活性突变相关（p = 0.038）。
这些数据表明，由于rs1801725处的失活性多态性导致CaSR对钙的敏感性降低，可能使高达20%的BC病例易患与循环高钙相关的更大和/或侵袭性更强的乳腺肿瘤。
