Abstract
Background
A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to ...radiotoxicity might improve risk prediction and inform functional mechanistic studies.
Methods
We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10−8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.
Results
Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10−10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10−10), and rs11122573 with hematuria (Pmeta = 1.8 × 10−8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10−6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.
Conclusions
This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the ...common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK and 368 cases from North America. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity=6.85×10(-9), odds ratio (OR)=6.61, 95% confidence interval (CI)=2.23-19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity=2.08×10(-4), OR=6.17, 95% CI=2.25-16.95; Pcombined=4.16×10(-10)). The inclusion of the third cohort gave unadjusted Pcombined=4.64×10(-11). These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Brachytherapy with iodine-125 (
I) has been extensively used as a conservative treatment for uveal melanoma (UM). Surgical technique for correct placement of episcleral radioactive plaques (ERP) in ...UM cases with posterior choroidal location and/or small size can be difficult and inaccurate. In this study, the correct positioning of plaques was assessed by intra-operative ultrasound control.
This was a longitudinal, retrospective study of consecutive 20 patients with UM (small-medium size and/or posterior location) who received
I brachytherapy. Location of plaques was adjusted by intra-operative ocular ultrasonography control. To perform ocular intra-operative ultrasonography, a 10 MHz probe was used to longitudinal and transverse bases in corresponding dummy plaques.
The study included 8 males and 12 females, with a mean age of 66.3 years (SD = 14.53), 5 right eyes (RE) and 15 left eyes (LE). In ultrasound examination, 4 UMs were of mushroom morphology and the rest nodular. Means of the size of UM by ultrasound were (mm): Lb: 10.60 (SD = 2.24) × Tb: 9.88 (SD = 1.54) × H: 4.02 (SD = 1.44) (3 cases corresponding to small size of collaborative ocular melanoma study (COMS), and 17 cases to medium). The plaques used were between 14 and 20 mm in diameter, with an average distance between the edge of greater base of the tumor and the edge of plate of 2.44 mm (SD = 0.34). It was necessary to surgically reposition the plaque in 4 cases (20%).
Intra-operative ultrasound control improves the accuracy of radioactive plaque placement for the treatment of medium-small UMs in posterior location. Probably, this technique should be applied in all cases of brachytherapy, regardless of the isotope chosen and the location of tumor mass, in order to perfectly adjust therapeutic position.
Several studies have identified single-nucleotide polymorphisms (SNPs) associated with adverse effects in non-small-cell lung cancer (NSCLC) patients treated with radiation therapy. Here, using an ...independent cohort, we aimed to validate the reported associations. We selected 23 SNPs in 17 genes previously associated with radiation-induced oesophagitis for validation in a cohort of 178 Spanish NSCLC patients. Of them, 18 SNPs were finally analysed, following the methods described in the original published studies. Two SNPs replicated their association with radiation-induced oesophagitis (rs7165790 located in the
gene: odds ratio (OR) = 0.16, 95% CI = 0.04-0.65,
-value = 0.010; rs4772468 at
: OR = 4.36, 95% CI = 1.15-16.46,
-value = 0.029). The SNP rs2868371 at
was also validated but displayed an opposite effect to the formerly described (OR = 3.72; 95% CI = 1.49-9.25;
-value = 0.004). Additionally, we tested a meta-analytic approach including our results and the previous datasets reported in the referenced publications. Twelve SNPs (including the two previously validated) retained their statistically significant association with radiation-induced oesophagitis. This study strengthens the role of inflammation and DNA double-strand break repair pathways in the risk prediction of developing radiation-induced oesophagitis in NSCLC patients. The validated variants are good candidates to be evaluated in risk prediction models for patient stratification based on their radiation susceptibility.
Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of ...differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort.
Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors.
Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype.
Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally.
EU-FP7.
Abstract Background and purpose We have performed a case-control study in 413 prostate cancer patients to test for association between TGFβ1 and the development of late normal-tissue toxicity among ...prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) Materials and methods Late gastrointestinal and genitourinary toxicities were assessed for at least two years after radiotherapy in 413 patients according to CTCAEvs3 scores. Codominant genotypic tests and haplotypic analyses were undertaken to evaluate the correlation between TGFβ1 SNPs rs1800469, rs1800470 and rs1800472 and radio-induced toxicity. Results Neither the SNPs nor the haplotypes were found to be associated with the risk of late toxicity. Conclusions We were able to exclude up to a 2-fold increase in the risk of developing late gastrointestinal and genitourinary radio-induced toxicity due to the TGFβ1 SNPs rs1800469 and rs1800470, as well as the two most frequent TGFβ1 haplotypes.
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•Acute radiation-induced toxicities (RITS) are heritable phenotypes and ∼29% of their variances are explained by common genetic variants.•Three potential novel mechanisms for RITs are ...exoribonuclease activity, inositol phosphate-mediated signaling, and drug catabolic process.•Using genetic markers is effective to understand the mechanism of acute RITs, and to predict acute RITs by employing polygenic risk scores.•Genetically enriched prediction model for RITs followed by radiation-dose adjustment contributes to attaining personalized radiotherapy.
We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC).
We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS.
From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %).
In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies.
Stereotactic radiosurgery undoubtedly represents an important therapeutic procedure for various intracranial pathologies, especially tumours, although they are not entirely complication-free. ...Radiosurgery have been considered a good management strategy for the majority of small-to-medium size vestibular schwannomas. The authors describe a case of high-grade glioma associated with a previous radiosurgery treatment for a vestibular schwannoma in a 69 year-old woman. A detailed description of these cases is provided, as well as a summary of the related literature.
Abstract Background and purpose We have performed a case–control study among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) in order to investigate the ...association between single nucleotide polymorphisms (SNPs), treatment and patient features with gastrointestinal and genitourinary acute toxicity. Material and methods A total of 698 patients were screened for 14 SNPs located in the ATM , ERCC2 , LIG4 , MLH1 and XRCC3 genes. Gastrointestinal and genitourinary toxicities were recorded prospectively using the Common Terminology Criteria for Adverse Events v3.0. Results The XRCC3 SNP rs1799794 (G/G OR = 5.65; 95% CI: 1.95–16.38; G/A OR = 2.75; 95% CI: 1.25–6.05; uncorrected p -value = 2.8 × 10−03 ; corrected p -value = 0.03; FDR q -value = 0.06) as well as the mean dose received by the rectum (OR = 1.06; 95% CI: 1.02–1.1; uncorrected p -value = 2.49 × 10−03 ; corrected p -value = 0.03; FDR q -value = 0.06) were significantly associated with gastrointestinal toxicity after correction for multiple testing. Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity (OR = 0.38; 95% CI: 0.18–0.71; uncorrected p -value = 4.95 × 10−03 ; corrected p -value = 0.03; FDR q -value = 0.08). Our study excludes the possibility of a >2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP, the rs1805386 and rs1805388 LIG4 markers, as well as all the SNPs evaluated in the ERCC2 , MLH1 and XRCC3 genes. Conclusions The XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT.
Abstract Background and purpose Mitochondrial DNA common variants have been reported to be associated with the development of radiation-induced toxicity. Using a large cohort of patients, we aimed to ...validate these findings by investigating the potential role of common European mitochondrial DNA SNPs (mtSNPs) to the development of radio-toxicity. Material and methods Overall acute and late toxicity data were assessed in a cohort of 606 prostate cancer patients by means of Standardized Total Average Toxicity (STAT) score. We carried out association tests between radiation toxicity and a selection of 15 mtSNPs (and the haplogroups defined by them). Results Statistically significant association between mtSNPs and haplogroups with toxicity could not be validated in our Spanish cohort. Conclusions The present study suggests that the mtDNA common variants analyzed are not associated with clinically relevant increases in risk of overall radiation-induced toxicity in prostate cancer patients.
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