Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of <i>TGFB1</i> and <i>TGFBR1</i>
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 rel...
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| Auteurs principaux: | , , , , , , , , , |
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| Format: | article |
| Langue: | EN |
| Publié: |
MDPI AG
2021
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| Sujets: | |
| Accès en ligne: | https://doaj.org/article/f25ac930b2264c5e89db1b4aecb2d0ea |
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| Résumé: | 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. |
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