Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.

<h4>Background</h4>Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and bio...

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Autores principales:	Laia Masvidal, Raquel Iniesta, Carla Casalà, Patricia Galván, Eva Rodríguez, Cinzia Lavarino, Jaume Mora, Carmen de Torres
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Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/108c900ae308469294afe805e126a740
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spelling	oai:doaj.org-article:108c900ae308469294afe805e126a7402021-11-18T07:52:14ZPolymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.1932-620310.1371/journal.pone.0059762https://doaj.org/article/108c900ae308469294afe805e126a7402013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23533647/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and biological features are associated with this diversity of clinical presentations. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor with a key role in calcium homeostasis. We have previously reported that it is expressed in benign, differentiated neuroblastic tumors, but silenced by genetic and epigenetic events in unfavorable neuroblastomas. We have now analyzed three functionally relevant polymorphisms clustered at the signal transduction region of the CaSR (rs1801725, rs1042636 and rs1801726) to assess if genetic variants producing a less active receptor are associated with more aggressive disease course.<h4>Methods</h4>Polymorphisms were analyzed in DNA samples from 65 patients using specific Taqman Genotyping Assays.<h4>Results</h4>Mildly inactivating variant rs1801725 was associated with clinical stage 4 (P = 0.002) and the histological subgroup of undifferentiated neuroblastomas (P = 0.046). Patients harboring this polymorphism had significantly lower overall (P = 0.022) and event-free survival (P = 0.01) rates than those who were homozygous for the most common allele among Caucasians. However, this single locus genotype was not independently associated with outcome in multivariate analyses. Conversely, the tri-locus haplotype TAC was independently associated with an increased risk of death in the entire cohort (Hazard Ratio = 2.45; 95% Confidence Interval [1.14-5.29]; P = 0.022) and also in patients diagnosed with neuroblastomas (Hazard Ratio = 2.74; 95% Confidence Interval [1.20-6.25]; P = 0.016).<h4>Conclusions</h4>The TAC haplotype includes the moderately inactivating variant rs1801725 and absence of the gain-of-function rs1042636 polymorphism. Thus, its association with metastatic disease and poor outcome would add to our previous data and further support that inactivation of the CaSR gene is a mechanism associated with neuroblastoma malignant behavior.Laia MasvidalRaquel IniestaCarla CasalàPatricia GalvánEva RodríguezCinzia LavarinoJaume MoraCarmen de TorresPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e59762 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laia Masvidal Raquel Iniesta Carla Casalà Patricia Galván Eva Rodríguez Cinzia Lavarino Jaume Mora Carmen de Torres Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
description	<h4>Background</h4>Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and biological features are associated with this diversity of clinical presentations. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor with a key role in calcium homeostasis. We have previously reported that it is expressed in benign, differentiated neuroblastic tumors, but silenced by genetic and epigenetic events in unfavorable neuroblastomas. We have now analyzed three functionally relevant polymorphisms clustered at the signal transduction region of the CaSR (rs1801725, rs1042636 and rs1801726) to assess if genetic variants producing a less active receptor are associated with more aggressive disease course.<h4>Methods</h4>Polymorphisms were analyzed in DNA samples from 65 patients using specific Taqman Genotyping Assays.<h4>Results</h4>Mildly inactivating variant rs1801725 was associated with clinical stage 4 (P = 0.002) and the histological subgroup of undifferentiated neuroblastomas (P = 0.046). Patients harboring this polymorphism had significantly lower overall (P = 0.022) and event-free survival (P = 0.01) rates than those who were homozygous for the most common allele among Caucasians. However, this single locus genotype was not independently associated with outcome in multivariate analyses. Conversely, the tri-locus haplotype TAC was independently associated with an increased risk of death in the entire cohort (Hazard Ratio = 2.45; 95% Confidence Interval [1.14-5.29]; P = 0.022) and also in patients diagnosed with neuroblastomas (Hazard Ratio = 2.74; 95% Confidence Interval [1.20-6.25]; P = 0.016).<h4>Conclusions</h4>The TAC haplotype includes the moderately inactivating variant rs1801725 and absence of the gain-of-function rs1042636 polymorphism. Thus, its association with metastatic disease and poor outcome would add to our previous data and further support that inactivation of the CaSR gene is a mechanism associated with neuroblastoma malignant behavior.
format	article
author	Laia Masvidal Raquel Iniesta Carla Casalà Patricia Galván Eva Rodríguez Cinzia Lavarino Jaume Mora Carmen de Torres
author_facet	Laia Masvidal Raquel Iniesta Carla Casalà Patricia Galván Eva Rodríguez Cinzia Lavarino Jaume Mora Carmen de Torres
author_sort	Laia Masvidal
title	Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
title_short	Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
title_full	Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
title_fullStr	Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
title_full_unstemmed	Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
title_sort	polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/108c900ae308469294afe805e126a740
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Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.

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