scholarly journals Calcium-Sensing Receptor Polymorphisms at rs1801725 are Associated with Increased Risk of Secondary Malignancies

2021 ◽  
Author(s):  
Ky'Era V. Actkins ◽  
Heather K. Beasley ◽  
Annika B. Faucon ◽  
Lea K. Davis ◽  
Amos M. Sakwe
Keyword(s):  
African Ancestry ◽  
Secondary Malignancies ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Secondary Neoplasms ◽  
Logistic Regression Models ◽  
Calcium Sensing ◽  
Skin Cancers ◽  
Increased Risk ◽  
Cancer Phenotypes

Purpose: 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. Methods: 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. Results: 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. Conclusions: Breast, prostate, and skin cancer patients with homozygous inactivating variants (TT genotype) at the CASR rs1801725 locus have 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.

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

2021 ◽  
Vol 11 (7) ◽  
pp. 642
Author(s):  
Ky’Era V. Actkins ◽  
Heather K. Beasley ◽  
Annika B. Faucon ◽  
Lea K. Davis ◽  
Amos M. Sakwe
Keyword(s):  
African Ancestry ◽  
Secondary Malignancies ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Secondary Neoplasms ◽  
Logistic Regression Models ◽  
Calcium Sensing ◽  
Increased Risk ◽  
High Calcium ◽  
Cancer Phenotypes

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.

Heterozygous Germline ATM Mutations Do Not Contribute to Radiation-Associated Malignancies After Hodgkin's Disease

1999 ◽  
Vol 17 (4) ◽  
pp. 1259-1259 ◽  
Author(s):  
Kim E. Nichols ◽  
Seth Levitz ◽  
Kristen E. Shannon ◽  
Doke C.R. Wahrer ◽  
Daphne W. Bell ◽  
...  
Keyword(s):  
Hodgkin's Disease ◽  
Genetic Factors ◽  
Mutational Analysis ◽  
Hodgkin’S Disease ◽  
Secondary Malignancies ◽  
Secondary Neoplasms ◽  
Exact Test ◽  
Secondary Tumors ◽  
Family Histories ◽  
Increased Risk

PURPOSE: The successful treatment of Hodgkin's disease has been associated with an increased incidence of secondary malignancies. To investigate whether genetic factors contribute to the development of secondary tumors, we collected family cancer histories and performed mutational analysis of the ataxia-telangiectasia (AT) gene, ATM, in a cohort of Hodgkin's disease survivors with secondary malignancies. ATM was chosen for evaluation because of the increased radiosensitivity of cells derived from AT patients and obligate heterozygotes and the epidemiologic observation that AT carriers are at increased risk for radiation-induced breast cancer. PATIENTS AND METHODS: Fifty-two patients who developed one or more neoplasms after treatment for Hodgkin's disease participated in this study. Personal and family histories of cancer were obtained through patient interviews and review of medical records. ATM mutational analysis was performed using a yeast-based protein truncation assay. RESULTS: Seventy-six secondary neoplasms were observed in this cohort of 52 Hodgkin's disease survivors, with 18 patients (35%) developing more than one secondary neoplasm. Positive family histories of cancer were present in 11 (21%) of 52 patients, compared with three (4%) of 68 Hodgkin's disease patients in a comparison cohort who did not develop secondary neoplasms (P = .008; Fisher's exact test). No germline ATM mutations were identified, resulting in an estimated AT carrier frequency in this population of 0% (90% confidence interval, 0% to 4%). CONCLUSION: Analysis of the number of tumors per individual and the family history of cancer in our cohort suggests that genetic factors may contribute to development of secondary neoplasms in a subset of Hodgkin's disease survivors. Mutational analysis, however, does not support a significant role for heterozygous truncating ATM mutations. Future studies evaluating other genes involved in DNA damage response pathways are warranted.

scholarly journals Association of preeclampsia with infant APOL1 genotype in African Americans

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Anna K. Miller ◽  
Timur Azhibekov ◽  
John F. O’Toole ◽  
John R. Sedor ◽  
Scott M. Williams ◽  
...  
Keyword(s):  
Black Women ◽  
African Ancestry ◽  
Significant Risk ◽  
The United States ◽  
Screening Tests ◽  
Case Definitions ◽  
Logistic Regression Models ◽  
Targeted Interventions ◽  
Risk Alleles ◽  
Increased Risk

Abstract Background Black women in the United States and Africa are at an increased risk for preeclampsia. Allelic variants in the gene for apolipoprotein LI, APOL1, are found only in populations of African ancestry, and have been shown to contribute significant risk for kidney disease. Recent studies suggest these APOL1 variants also may contribute risk for preeclampsia. Methods The association of preeclampsia with carriage of APOL1 risk alleles was evaluated in a case-control study of deliveries from black women at a single center in Cleveland, Ohio that included gross and histopathologic evaluations of placental tissues (395 cases and 282 controls). Using logistic regression models, associations between fetal APOL1 genotype and preeclampsia were evaluated using several case definitions based on prematurity and severity of preeclampsia, with uncomplicated term pregnancies as controls. Associations between APOL1 genotype and pathological features were also examined. Results The infant APOL1 genotype was significantly associated with preeclampsia in a dominant inheritance pattern with odds ratio of 1.41 (P=0.029, 95% CI 1.037, 1.926). Stratifying preeclampsia cases by preterm birth, significant associations were detected for both recessive (O.R.=1.70, P=0.038) and additive (O.R.=1.33, P=0.028) inheritance patterns. APOL1 genotype, however, was not significantly associated with pathological changes or other perinatal observations. Conclusions Preeclampsia appears to be another disease associated with APOL1 variants, however, further studies are needed to increase confidence in the mode of inheritance. By understanding the association of APOL1 variants with preeclampsia, genetic screening tests for APOL1 may be useful to predict at-risk pregnancies and targeted interventions may be developed to improve pregnancy outcomes.

scholarly journals SINGLE-NUCLEOTIDE POLYMORPHISMS OF CALCIUM-SENSING RECEPTOR ENCODING GENE ASSOCIATED WITH CALCIUM KIDNEY STONE DISEASE IN BABYLON PROVINCE

2018 ◽  
Vol 11 (2) ◽  
pp. 417 ◽  
Author(s):  
Zahraa Isam ◽  
Rabab Omran ◽  
Ammad Hassan Mahmood
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Kidney Stone ◽  
Stone Disease ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Kidney Stone Disease ◽  
Calcium Sensing

  Objective: The calcium-sensing receptor (CASR) is a G-protein-coupled receptor that is mainly expressed in the parathyroid and the kidneys where it regulates parathyroid hormone secretion and renal tubular calcium reabsorption. Inactivating and activating CASR gene due to mutations severally caused hypercalcemia or hypocalcemia disorders. The aim of the study was to investigate the risk factor of CASR rs1801725 (Ala986Ser) patients with renal disease.Method: The blood samples were collected from 100 patients and divided into two groups, each one containing 50 samples; chronic kidney disease and end-stage renal disease, who admitted Merjan Teaching Hospital in Babylon Province, Iraq, from February to July 2016. In addition, healthy persons as a control group (50 samples). Genotyping of CASR single-nucleotide polymorphisms (SNP) was performed using a polymerase chain reaction technique, followed by single-strand conformation polymorphism. Accordingly, these DNA polymorphisms were confirmed using DNA sequencing.Results: The conformational haplotypes of CASR, exon7 NCBI Primer3plus reference were obtained in three patterns, including two, three, and four bands, due to the presence SNPs within the studied region. These SNPs leads to change three amino acid residues of CASR, including amino acid substitutions were Ala 128→ Ser 128, Leu 155→Tye 155, and Leu 156→ Ser 156 that may affect or modified the tertiary structure of the receptor, subsequently the function like the affinity to calcium ion may be effected.Conclusion: These results suggest that the variants of CASR SNP, namely, rs1801725 might be involved in susceptibility to kidney stone disease.

Chronic Lymphocytic Leukemia-Associated Chromosomal Abnormalities and Risk of Secondary Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5636-5636
Author(s):  
Shahzad Raza ◽  
Paul J Hampel ◽  
Belal Firwana ◽  
Zhen Wang ◽  
Yasar Shad ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Secondary Malignancy ◽  
Secondary Malignancies ◽  
Skin Cancers ◽  
Increased Risk ◽  
Trisomy 12 ◽  
13Q Deletion ◽  
Melanoma Skin

Abstract Introduction: Incidence of secondary malignant neoplasm in patients with chronic lymphocytic leukemia (CLL) is already established. Genetic predisposition has been considered to be a possible contributory factor for the preponderance of second cancers in this population. In the present study, we examined the frequency, characteristics, and clinical outcomes of secondary malignancies in patients with CLL based on their Interphase fluorescence in situ hybridization (FISH) panel. Methods: We reviewed the medical records of consecutive patients with CLL observed or treated at Ellis Fischel Cancer Center during the period from 2007-2014. We collected demographic data, CLL Rai stage, treatment history, Interphase fluorescence in situ hybridization (FISH) panel results and the presence of a secondary malignancy (skin cancers, solid tumors and hematologic malignancy excluding CLL transformation).Our aim was to investigate the association between secondary malignancy and chromosomal abnormalities and other risk factors using Chi2test for categorical variables and Wilcoxon rank-sum test for continuous variables. Cox proportional hazard models and logistic regression models were used to evaluate risk factors of developing secondary malignancy and overall survival. Results: We identified 142 CLL patients who were either observed (n=62) or had a history of treatment (n=80) for CLL. 67% were male and 33% were female. 85% of patients were Caucasians, 10% African Americans, and 5% other. Familial CLL was present in 6% of cases. 51% of patients were non-smokers. 5% of patients had cancers preceding the diagnosis of CLL (non-melanoma skin cancers=3, melanoma=1, Hodgkin's lymphoma=1, Prostate=2). 28% of patients developed secondary malignancies after the diagnosis of CLL; among them non-melanoma skin cancers were the most common (78%), followed by cutaneous melanoma (9.5%) and papillary thyroid cancer (4.7%). Other malignancies included lung (2.3%), kidney (2.3%), prostate (2.3%) and ocular melanoma (2.3%). 12% patients had aggressive non-melanoma recurrent skin cancers that require multiple treatments along-with systemic therapy for progressive CLL. CLL-FISH panel at diagnosis was available in 98 patients. Among these patients,13q deletion was present in 45%. Within the 13q deletion group, secondary malignancy was noted in 50% during a median follow up of 7 years. All cases of papillary thyroid cancers were also present in 13q deletion. In contrast, 11q deletion was detected in 15% and trisomy 12 in 18% of patients with incidence of secondary malignancy 40% and 10%, respectively. No solid malignancy other than skin was identified in the 11q deletion and trisomy 12 groups. 17p deletion was present in 5% of cases and 60% of 17p deletion cases had secondary cancers (skin 80%). Normal FISH panel was present in 17% cases and 20% of normal FISH had secondary malignancy (solid 10%, skin 10%). The median overall survival time is 6 years for the entire cohort (IRQ: 3-9 years). Secondary malignancy was associated with worse overall survival (OS) (HR=0.57, 95% CI:0.33-0.98, p=0.04) compare to patients who did not have secondary malignancy. The risk of secondary malignancy is increased in patients with advanced age (OR=1.05, 95% CI:1.00-1.10, p=0.04) and in those who were treated with alkylating agent for CLL OR=6.62, 95% CI:2.08-21.03, p=0.001. However, there were no significant difference on risk of developing secondary malignancy based on specific chromosomal FISH result, Rai stage, smoking, family history and gender. Conclusion: Secondary malignancies are frequent in patients with detectable chromosome abnormality on FISH panel. However, the increased risk of secondary malignancy does not correlate with specific cytogenetic abnormality. Non melanoma skin cancers are exceedingly common in CLL patients and carries aggressive couse in progressive CLL patients. Larger studies are required to identify subtype of CLL based on integrated mutational and cytogenetic subgroup that are at increased risk of specific secondary malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Calcium-sensing receptor mutations and denaturing high performance liquid chromatography

2009 ◽  
Vol 42 (4) ◽  
pp. 331-339 ◽  
Author(s):  
David E C Cole ◽  
Francisco H J Yun ◽  
Betty Y L Wong ◽  
Andrew Y Shuen ◽  
Ronald A Booth ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
High Performance ◽  
Mineral Metabolism ◽  
Direct Sequencing ◽  
Effective Means ◽  
Melting Curve ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

The calcium-sensing receptor (CASR), a plasma membrane G-protein-coupled receptor, is expressed in parathyroid gland and kidney, and controls systemic calcium homeostasis. Inactivating CASR mutations are associated with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism, and activating mutations cause autosomal dominant hypocalcemia (ADH). CASR mutation identification plays an important role in the clinical management of mineral metabolism disorders. We describe here a high-throughput method using screening with denaturing high performance liquid chromatography (DHPLC) to initially interrogate 12 amplicons covering translated exons and exon/intron boundaries, followed by sequencing of any amplicon with a modified melting curve relative to wild type, and direct sequencing of a 13th amplicon encoding the COOH-terminal tail to distinguish causative mutations from three common missense single nucleotide polymorphisms. A blinded analysis of 32 positive controls representing mutations throughout the CASR sequence, as well as 22 negative controls, yielded a concordance rate of 100%. We report eight novel and five recurrent FHH mutations, along with six novel and two recurrent ADH mutations. Thus, DHPLC provides a rapid and effective means to screen for CASR mutations.

Susceptibility to Alkylator-Induced Cancer Is a Heritable Trait.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3266-3266
Author(s):  
Deepa Edwin ◽  
Timothy S. Fenske ◽  
Christine McMahon ◽  
Vikram Mathews ◽  
Molly Bogue ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lung Adenocarcinoma ◽  
Cancer Susceptibility ◽  
Soft Tissue Sarcomas ◽  
Inbred Strains ◽  
Primary Diagnosis ◽  
Nucleotide Polymorphisms ◽  
Secondary Neoplasms ◽  
Heritable Trait ◽  
Cancer Phenotypes

Abstract Secondary malignancies are a serious adverse consequence of alkylator chemotherapy treatment. The incidence of secondary hematopoietic malignancies (t-MDS/AML) exceeds 11% in several recent reports. Secondary solid tumors (lung, breast) also occur after alkylator exposure. While patient age, primary diagnosis, and chemotherapy dose are established risk factors, there is increasing evidence that germline genetic factors are also important in determining risk. The genetic basis of susceptibility to alkylator-induced secondary neoplasms is poorly understood. Most studies have focused on genes in drug metabolic pathways. A limited number of genetic polymorphisms with modest impact on risk for alkylator-induced cancer have been reported. We hypothesize that other genetic contributors to alkylator-induced cancer susceptibility have not yet been identified. To screen genome-wide for novel heritable susceptibility factors, we established a mouse model of alkylator-induced malignancy. In collaboration with the Mouse Phenome Project, we exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). Mice (n=12 per strain) received two doses of ENU (100mg/kg, IP) or no treatment (n=12 per strain) at 9 and 10 weeks of age. ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared to a background incidence of 8% spontaneous tumors in 240 strain, age, and sex-matched control mice (relative risk = 8.4, p< 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H2 = 0.25, implying that 25% of cancer risk is heritable), T-cell lymphoma (H2 = 0.19), and myeloid malignancies (H2 = 0.10). The development of hematopoietic tumors (either lymphoid or myeloid) was negatively associated with the likelihood of developing gastrointestinal or lung adenocarcinoma. In silico quantitative trait locus (QTL) mapping was used to identify genomic intervals associated with cancer susceptibility. Strains were segregated by haplotype using a panel of 10,900 single nucleotide polymorphisms (SNPs). Differences in cancer susceptibility between haplotypes were assessed by ANOVA. After correcting for false detection, genomic intervals significantly associated with specific cancer phenotypes were identified. Preliminary analysis linked lung cancer susceptibility to four intervals on chromosomes 1,2,6, and 12. The latter interval contains Ahr, a highly polymorphic gene encoding the aryl hydrocarbon receptor previously implicated in carcinogenicity of environmental toxins. Lymphoma susceptibility was linked to two regions on chromosomes 3 and 18. The latter contains a member of the frizzled family of Wnt receptors. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to inform clinical treatment decisions.

scholarly journals The G Allele of CaSR R990G Polymorphism Increases Susceptibility to Urolithiasis and Hypercalciuria: Evidences from a Comprehensive Meta-Analysis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Kang Liu ◽  
Xiaolan Wang ◽  
Jiaxin Ye ◽  
Chao Qin ◽  
Pengfei Shao ◽  
...  
Keyword(s):  
Calcium Concentration ◽  
Protective Factor ◽  
Meta Analysis ◽  
Receptor Gene ◽  
Healthy Population ◽  
Case Control Studies ◽  
Calcium Sensing Receptor ◽  
Urine Calcium ◽  
Calcium Sensing ◽  
Increased Risk

Background. The calcium-sensing receptor gene (CaSR) is a candidate to explain urolithiasis. A number of case-control studies were conducted to investigate associations between CaSR polymorphisms with risks of hypercalciuria and urolithiasis in humans. But the results were still inconsistent.Methods. A meta-analysis was performed to address this issue. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations between CaSR polymorphisms and the risk of urolithiasis. The pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of CaSR polymorphisms and urine calcium concentration.Results. For urolithiasis association, the SS genotype of A986S polymorphism was a risk factor for urolithiasis in Asians and PHPT patients, but a protective factor in Caucasians. The GG genotype of R990 polymorphism was associated with an increased risk of urolithiasis, especially in Caucasians and healthy population. Regarding urine calcium concentration association, individuals with the G allele had a higher level of urine calcium than the noncarriers.Conclusions. This meta-analysis revealed that the G allele of CaSR R990G polymorphism increases susceptibility to urolithiasis and hypercalciuria. The A986S and Q1011E polymorphisms were associated with urolithiasis and hypercalciuria in specific populations.

scholarly journals Association between calcium-sensing receptor (CaSR) R990G, CaSR A986S, and CaSR Q1011E gene polymorphisms and the risk of urolithiasis: a meta-analysis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Besut Daryanto ◽  
Basuki Bambang Purnomo ◽  
Atma Gunawan ◽  
Fredo Tamara ◽  
Saga Aditya Hutama ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Meta Analysis ◽  
Random Effect ◽  
Random Effect Model ◽  
Group Analysis ◽  
Asian Population ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Casr Gene ◽  
Calcium Sensing

Abstract Backgrounds In the last two decades, studies have been widely carried out to assess the association between single-nucleotide polymorphisms (SNPs) of calcium-sensing receptor (CaSR) gene in exon 7 and the risk of urolithiasis. However, inconsistency across the studies was reported. Therefore, our current study aimed to perform a meta-analysis concerning the association between the risk of urolithiasis and the gene polymorphisms of CaSR R990G, CaSR A986S, and CaSR Q1011E. Methods Published papers from PubMed, Embase, Cohcrane, and Web of science were included for the study, and they were analyzed using fixed or random effect model. Results A total of 11 papers consisting of eight papers evaluating CaSR R990G, nine papers evaluating CaSR A986S, and five papers evaluating CaSR Q1011E were included in our analysis. Our pooled calculation found that protective effect against urolithiasis was observed in R allele and RR genotype of CaSR R990G and A allele and AA genotype of CaSR A986S. Conversely, increased susceptibility to urolithiasis was found in G allele and RG genotype of CaSR R990G and S allele of CaSR A986S. Interestingly, our findings in sub-group analysis confirmed that the correlation between CaSR R990G and urolithiasis was found in Caucasian population. Meanwhile, in Asian population, the association was observed in CaSR A986S. Conclusions CaSR R990G and CaSR A986S, but not CaSR Q1011E, are associated with the risk of urolithiasis.

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