Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of TGFB1 and TGFBR1

Genetic variability in transforming growth factor beta pathway (TGFB) was suggested to affect adverse events of radiotherapy. We investigated comprehensive variability in TGFB1 (gene coding for TGFβ1 ligand) and TGFBR1 (TGFβ receptor-1) in rel...

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Autores principales:	Manuel Guhlich, Laura Hubert, Caroline Patricia Nadine Mergler, Margret Rave-Fraenk, Leif Hendrik Dröge, Martin Leu, Heinz Schmidberger, Stefan Rieken, Andrea Hille, Markus Anton Schirmer
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	radiotherapy side effects toxicity prostate cancer biomarkers TGFB Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f25ac930b2264c5e89db1b4aecb2d0ea
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spelling	oai:doaj.org-article:f25ac930b2264c5e89db1b4aecb2d0ea2021-11-11T15:36:14ZIdentification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>10.3390/cancers132155852072-6694https://doaj.org/article/f25ac930b2264c5e89db1b4aecb2d0ea2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5585https://doaj.org/toc/2072-6694Genetic variability in transforming growth factor beta pathway (<i>TGFB</i>) was suggested to affect adverse events of radiotherapy. We investigated comprehensive variability in <i>TGFB1</i> (gene coding for TGFβ1 ligand) and <i>TGFBR1</i> (TGFβ receptor-1) in relation to radiotoxicity. Prostate cancer patients treated with primary radiotherapy (<i>n</i> = 240) were surveyed for acute and late toxicity. Germline polymorphisms (<i>n</i> = 40) selected to cover the common genetic variability in <i>TGFB1</i> and <i>TGFBR1</i> were analyzed in peripheral blood cells. Human lymphoblastoid cell lines (LCLs) were used to evaluate a possible impact of <i>TGFB1</i> and <i>TGFBR1</i> genetic polymorphisms to DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, rs10512263 in <i>TGFBR1</i> showed a statistically significant association with acute radiation toxicity. Carriers of the <i>Cytosine (C)</i>-variant allele (<i>n</i> = 35) featured a risk ratio of 2.17 (95%-CI 1.41–3.31) for acute toxicity ≥ °2 compared to <i>Thymine/Thymine (TT)-</i>wild type individuals (<i>n</i> = 205). Reduced DNA repair capacity in the presence of the <i>C</i>-allele of rs10512263 might be a mechanistic explanation as demonstrated in LCLs following irradiation. The risk for late radiotoxicity was increased by carrying at least two risk genotypes at three polymorphic sites, including Leu10Pro in <i>TGFB1</i>. Via comprehensive genotyping of <i>TGFB1</i> and <i>TGFBR1</i>, promising biomarkers for radiotoxicity in prostate cancer were identified.Manuel GuhlichLaura HubertCaroline Patricia Nadine MerglerMargret Rave-FraenkLeif Hendrik DrögeMartin LeuHeinz SchmidbergerStefan RiekenAndrea HilleMarkus Anton SchirmerMDPI AGarticleradiotherapyside effectstoxicityprostate cancerbiomarkersTGFBNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5585, p 5585 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	radiotherapy side effects toxicity prostate cancer biomarkers TGFB Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	radiotherapy side effects toxicity prostate cancer biomarkers TGFB Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Manuel Guhlich Laura Hubert Caroline Patricia Nadine Mergler Margret Rave-Fraenk Leif Hendrik Dröge Martin Leu Heinz Schmidberger Stefan Rieken Andrea Hille Markus Anton Schirmer Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
description	Genetic variability in transforming growth factor beta pathway (<i>TGFB</i>) was suggested to affect adverse events of radiotherapy. We investigated comprehensive variability in <i>TGFB1</i> (gene coding for TGFβ1 ligand) and <i>TGFBR1</i> (TGFβ receptor-1) in relation to radiotoxicity. Prostate cancer patients treated with primary radiotherapy (<i>n</i> = 240) were surveyed for acute and late toxicity. Germline polymorphisms (<i>n</i> = 40) selected to cover the common genetic variability in <i>TGFB1</i> and <i>TGFBR1</i> were analyzed in peripheral blood cells. Human lymphoblastoid cell lines (LCLs) were used to evaluate a possible impact of <i>TGFB1</i> and <i>TGFBR1</i> genetic polymorphisms to DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, rs10512263 in <i>TGFBR1</i> showed a statistically significant association with acute radiation toxicity. Carriers of the <i>Cytosine (C)</i>-variant allele (<i>n</i> = 35) featured a risk ratio of 2.17 (95%-CI 1.41–3.31) for acute toxicity ≥ °2 compared to <i>Thymine/Thymine (TT)-</i>wild type individuals (<i>n</i> = 205). Reduced DNA repair capacity in the presence of the <i>C</i>-allele of rs10512263 might be a mechanistic explanation as demonstrated in LCLs following irradiation. The risk for late radiotoxicity was increased by carrying at least two risk genotypes at three polymorphic sites, including Leu10Pro in <i>TGFB1</i>. Via comprehensive genotyping of <i>TGFB1</i> and <i>TGFBR1</i>, promising biomarkers for radiotoxicity in prostate cancer were identified.
format	article
author	Manuel Guhlich Laura Hubert Caroline Patricia Nadine Mergler Margret Rave-Fraenk Leif Hendrik Dröge Martin Leu Heinz Schmidberger Stefan Rieken Andrea Hille Markus Anton Schirmer
author_facet	Manuel Guhlich Laura Hubert Caroline Patricia Nadine Mergler Margret Rave-Fraenk Leif Hendrik Dröge Martin Leu Heinz Schmidberger Stefan Rieken Andrea Hille Markus Anton Schirmer
author_sort	Manuel Guhlich
title	Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
title_short	Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
title_full	Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
title_fullStr	Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
title_full_unstemmed	Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
title_sort	identification of risk loci for radiotoxicity in prostate cancer by comprehensive genotyping of <i>tgfb1</i> and <i>tgfbr1</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f25ac930b2264c5e89db1b4aecb2d0ea
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Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>

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