Calcium-sensing receptor A986S polymorphism in human rectal cancer

Szabó, Gábor; Cseh, Károly; Mucsi, István; Takács, István; Dworák, O.; Winkler, G.; Sződy, Róbert; Tislér, András; Lakatos, Péter L.

doi:10.1007/s003840100359

Cited by 20 publications

(27 citation statements)

References 22 publications

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“…Accordingly, these data support the hypothesis that the CaSR gene A986S variant might have a role in pathogenesis of CRC. Studies of the effect of CaSR gene A986S variant on colorectal, colon, or rectal cancer have been inconclusive (Speer et al, 2002;Fuszek et al, 2004;Bacsi et al, 2008;Dong et al, 2008;Jenab et al, 2009). Consistent with our findings, most previous studies found no association between this variant and CRC.…”

Section: Discussionsupporting

confidence: 88%

“…We did not observe significant associations for the A986S variant in the overall analysis and in the analyses stratified by tumor site, sex, or BMI. In work by Speer et al (2002), the authors reported that there was no association between the A986S variant and rectal cancer risk in a population including 56 cases with rectal cancer and 112 controls. However, they found an association between the variant and more advanced rectal tumors.…”

Section: Discussionmentioning

confidence: 99%

“…CaSR appears to play a tumor suppressor role in CRC and has a critical role in the maintenance of calcium homeostasis (Sarkar and Kumar, 2012;Ward et al, 2012) by modulating parathyroid hormone (PTH) secretion from the parathyroid glands (Saidak et al, 2009). In recent years, the relationship between CaSR gene polymorphisms and CRC risk has garnered a great deal of attention and association studies of CaSR gene rs1801725 (A986S) variant have been performed to investigate its implication with CRC risk, but despite the biological plausibility the results are inconsistent (Speer et al, 2002;Fuszek et al, 2004;Bacsi et al, 2008;Dong et al, 2008;Jenab et al, 2009) and the role of this gene in the etiology of CRC is still equivocal. Some studies (Speer et al, 2002;Fuszek et al, 2004;Dong et al, 2008;Jenab et al, 2009) have found no association, other investigations (Bacsi et al, 2008) have reported significant associations between the A986S variant and the risk of CRC.…”

Section: Introductionmentioning

confidence: 99%

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Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Mahmoudi¹,

Karimi²,

Arkani³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Substantial evidence from epidemiological studies has suggested that increased levels of calcium may play a protective role against colorectal cancer (CRC). Given the vital role of calcium sensing receptor (CaSR) and parathyroid hormone (PTH) in the maintenance of calcium homeostasis, we explored whether the rs1801725 (A986S) variant located in exon 7 of the CaSR gene and the rs6256 variant located in exon 3 of PTH gene might be associated with CRC risk. Materials and Methods: In this study 860 subjects including 350 cases with CRC and 510 controls were enrolled and genotyped using PCR-RFLP methods. Results: We observed no significant difference in genotype or allele frequencies between the cases with CRC and controls for both CaSR and PTH genes either before or after adjustment for confounding factors including age, BMI, sex, smoking status, and family history of CRC. Furthermore, no evidence for effect modification of any association of rs1801725 and rs6256 variants and CRC by BMI, sex, or tumor site was observed. In addition, there was no significant difference in genotype and allele frequencies between the normal weight (BMI <25 kg/m 2 ) cases and overweight/ obese (BMI ≥25 kg/m 2 ) cases for the two SNPs. Conclusions: These data indicated that the CaSR gene A986S variant is not a genetic contributor to CRC risk in the Iranian population. Furthermore, our results suggest for the first time that PTH gene variant does not affect CRC risk. Nonetheless, further studies with larger sample size are needed to validate these findings.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Mahmoudi¹,

Karimi²,

Arkani³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…The promoter region of the CASR gene contains a vitamin D response element, suggesting a potential regulation by vitamin D (44). CASR polymorphisms have been shown to be associated with the risk of colorectal adenomas (26) and increasing stage of rectal cancer (45). However, findings were overall null in a recent comprehensive study of various CASR polymorphisms and haplotypes and the risk of colon cancer (46).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations

Jenab

McKay

Bueno-de-Mesquita

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the Received 4/7/09; revised 5/29/09; accepted 7/9/09; published OnlineFirst 8/25/09.

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“…Indeed, the CaR, apart from its pivotal role in systemic calcium homeostasis, is now being considered as a possible key regulator of cell proliferation, differentiation and chemotaxis (Brown, 2000;Chattopadhyay, 2000). Moreover, its deregulation is causally linked to colon cancer (Speer et al, 2002). Given the complexity of the AT phenotype, it is not surprising that a number of investigations have been undertaken to explore a possible functional link between ATM and calcium signaling.…”

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confidence: 99%

Aberrant sensing of extracellular Ca2+ by cultured ataxia telangiectasia fibroblasts

et al. 2003

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Ataxia telangiectasia (AT) is a human hereditary syndrome whose underlying gene product, ataxia telangiectasia mutated (ATM) protein kinase, is involved in multiple intracellular signaling pathways. We demonstrated previously that AT fibroblasts are defective in intracellular Ca 2+ mobilization in response to both stressinducing and mitogenic stimuli. To extend these findings, normal and AT cells were exposed to serum in the presence of different concentrations of extracellular Ca 2+ ([Ca 2+ ] o ), and release of intracellular Ca 2+ , activation of calmodulin-dependent protein kinase II and phosphorylation of kinases ERK1 and 2 were monitored. When maintained in high [Ca 2+ ] o (0.42 mm), normal fibroblasts responded to serum introduction more rapidly and efficiently than did AT cells. Unexpectedly, decreasing the [Ca 2+ ] o in the medium had a diametrically opposite effect. Under low [Ca 2+ ] o (0.0022 mm) conditions, normal cells were slow and inefficient in their responses, whereas AT cells showed a substantial improvement in all three end points. These findings demonstrate that loss of ATM kinase function deregulates the extracellular calciumsensing receptor (CaR). This malfunction presumably arises from a post-transcriptional event, since CaR mRNA proved to be normal in AT cells. Together, our data suggest that ATM may mediate cell response to mitogenic factors by tightly regulating the set point of the CaR and thereby modulating the crosstalk between this metabotropic receptor and growth factor receptors. Alternatively, the faulty sensing of extracellular calcium in AT cells may be secondary to a state of chronic oxidative stress attributable to ATM deficiency.

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Calcium-sensing receptor A986S polymorphism in human rectal cancer

Abstract: Our observation raises the possibility that genetic alterations of CaSR influence the pathogenesis of rectal cancer.

Cited by 20 publications

References 22 publications

Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations

Aberrant sensing of extracellular Ca2+ by cultured ataxia telangiectasia fibroblasts

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