Abstract
Simple SummaryGenetic 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.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.
Highlights
Prostate cancer is the most frequent malignancy in male patients and accounts for about 20% of new cases per year [1]
We demonstrate for the first time, to the best of our knowledge, a strong association of a single genetic marker in TGFBR1 with acute toxicity and provide functional data for putative mechanistic actions
We applied comprehensive genotyping for TGFB1 and TGFBR1 polymorphisms in relation to acute and late side effects of radiotherapy in prostate cancer
Summary
Prostate cancer is the most frequent malignancy in male patients and accounts for about 20% of new cases per year [1]. Acute and late side effects of radiotherapy usually affect the rectum and the urinary bladder [5] Such events occurring up to three months upon therapy completion are defined as acute, thereafter as late toxicity. Alongside non-genetic factors, such as patient age, radiation technique, dosage, and the extent of the irradiated field, the intrinsic radiosensitivity driven by the genetic make-up is thought to be a major contributor for radiation toxicity [8,9]. Integration of these different kinds of information seems to enhance prediction of adverse radiation effects [10]. Identification of genetic variation linked to adverse effects of irradiation may allow to define individuals at risk prior to therapy [11]
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