Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of
| Autor: | Heinz Schmidberger, Martin Leu, Caroline Patricia Nadine Mergler, Stefan Rieken, Margret Rave-Fraenk, Laura Hubert, Leif Hendrik Dröge, Andrea Hille, Manuel Guhlich, M Schirmer |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
TGFB DNA repair SNP Leu10Pro Article 03 medical and health sciences Prostate cancer chemistry.chemical_compound 0302 clinical medicine Genotype Medicine Genetic variability Allele Genotyping RC254-282 radiotherapy TGBF1 030304 developmental biology 0303 health sciences irradiation business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens toxicity biomarkers LCL medicine.disease prostate cancer Acute toxicity 3. Good health rs10512263 side effects Oncology chemistry 030220 oncology & carcinogenesis Cancer research business Cytosine |
| Zdroj: | Cancers Volume 13 Issue 21 Cancers, Vol 13, Iss 5585, p 5585 (2021) |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Genetic variability in transforming growth factor beta pathway (TGFB) has been reported to affect adverse events in radiotherapy. We investigated 40 germline polymorphisms in peripheral blood cells, covering the entire common genetic variability in the TGFβ1 ligand (gene TGFB1) and the TGFβ receptor-1 (TGFBR1) in 240 patients treated with primary radiotherapy for prostate cancer. Human lymphoblastoid cell lines (LCLs) were used to assess whether TGFB1 and TGFBR1 polymorphisms impact DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, for one polymorphism (rs10512263 in TGFBR1, C-variant allele, n = 35), a statistically significant association with acute radiation toxicity was observed. As a possible mechanistic explanation, reduced DNA repair capacity in carriers of the C-allele after irradiation in LCLs was discovered. This finding has a possible relevance for a plethora of (patho)physiological conditions. Abstract 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 relation to radiotoxicity. Prostate cancer patients treated with primary radiotherapy (n = 240) were surveyed for acute and late toxicity. Germline polymorphisms (n = 40) selected to cover the common genetic variability in TGFB1 and TGFBR1 were analyzed in peripheral blood cells. Human lymphoblastoid cell lines (LCLs) were used to evaluate a possible impact of TGFB1 and TGFBR1 genetic polymorphisms to DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, rs10512263 in TGFBR1 showed a statistically significant association with acute radiation toxicity. Carriers of the Cytosine (C)-variant allele (n = 35) featured a risk ratio of 2.17 (95%-CI 1.41–3.31) for acute toxicity ≥ °2 compared to Thymine/Thymine (TT)-wild type individuals (n = 205). Reduced DNA repair capacity in the presence of the C-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 TGFB1. Via comprehensive genotyping of TGFB1 and TGFBR1, promising biomarkers for radiotoxicity in prostate cancer were identified. |
| Databáze: | OpenAIRE |
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