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Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors

OBJECTIVE/PURPOSE: The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease wit...

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Autores principales: Re, Agnese, Ferraù, Francesco, Cafiero, Concetta, Spagnolo, Federica, Barresi, Valeria, Romeo, Daniela Petronilla, Ragonese, Marta, Grassi, Claudio, Pontecorvi, Alfredo, Farsetti, Antonella, Cannavò, Salvatore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689685/
https://www.ncbi.nlm.nih.gov/pubmed/33281746
http://dx.doi.org/10.3389/fendo.2020.591039
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author Re, Agnese
Ferraù, Francesco
Cafiero, Concetta
Spagnolo, Federica
Barresi, Valeria
Romeo, Daniela Petronilla
Ragonese, Marta
Grassi, Claudio
Pontecorvi, Alfredo
Farsetti, Antonella
Cannavò, Salvatore
author_facet Re, Agnese
Ferraù, Francesco
Cafiero, Concetta
Spagnolo, Federica
Barresi, Valeria
Romeo, Daniela Petronilla
Ragonese, Marta
Grassi, Claudio
Pontecorvi, Alfredo
Farsetti, Antonella
Cannavò, Salvatore
author_sort Re, Agnese
collection PubMed
description OBJECTIVE/PURPOSE: The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region. METHODS: A cohort of 13 patients aged 20–76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients’ germline DNA as well as normal pituitary tissue as reference control. RESULTS: A degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5’ upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus. CONCLUSION: This is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.
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spelling pubmed-76896852020-12-04 Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors Re, Agnese Ferraù, Francesco Cafiero, Concetta Spagnolo, Federica Barresi, Valeria Romeo, Daniela Petronilla Ragonese, Marta Grassi, Claudio Pontecorvi, Alfredo Farsetti, Antonella Cannavò, Salvatore Front Endocrinol (Lausanne) Endocrinology OBJECTIVE/PURPOSE: The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region. METHODS: A cohort of 13 patients aged 20–76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients’ germline DNA as well as normal pituitary tissue as reference control. RESULTS: A degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5’ upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus. CONCLUSION: This is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified. Frontiers Media S.A. 2020-11-12 /pmc/articles/PMC7689685/ /pubmed/33281746 http://dx.doi.org/10.3389/fendo.2020.591039 Text en Copyright © 2020 Re, Ferraù, Cafiero, Spagnolo, Barresi, Romeo, Ragonese, Grassi, Pontecorvi, Farsetti and Cannavò http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Re, Agnese
Ferraù, Francesco
Cafiero, Concetta
Spagnolo, Federica
Barresi, Valeria
Romeo, Daniela Petronilla
Ragonese, Marta
Grassi, Claudio
Pontecorvi, Alfredo
Farsetti, Antonella
Cannavò, Salvatore
Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title_full Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title_fullStr Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title_full_unstemmed Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title_short Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors
title_sort somatic deletion in exon 10 of aryl hydrocarbon receptor gene in human gh-secreting pituitary tumors
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689685/
https://www.ncbi.nlm.nih.gov/pubmed/33281746
http://dx.doi.org/10.3389/fendo.2020.591039
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