The association between TGF-ß1 polymorphisms and radiation pneumonia in lung cancer patients treated with definitive radiotherapy: a meta-analysis.

BACKGROUND: Previous studies investigating the association between TGF-ß1 polymorphisms and Radiation Pneumonia (RP) risk have provided inconsistent results. The aim of our study was to assess the association between the TGF-ß1 genes C509T, G915C and T869C polymorphisms and risk of RP in lung cancer patients treated with definitive radiotherapy. METHODS: Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before September 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for TGF-ß1 polymorphisms and RP were calculated in a fixed-effects model or a random-effects model when appropriate. RESULTS: Ultimately, each 7 studies were found to be eligible for meta-analyses of C509T, G915C and T869C, respectively. Our analysis suggested that the variant genotypes of T869C were associated with a significantly increased RP risk in dominant model (OR = 0.59, 95% CI = 0.45-0.79) and CT vs. TT model (OR = 0.47, 95% CI = 0.32-0.69). In the subgroup analyses by ethnicity/country, a significantly increased risk was observed among Caucasians. For C509T and G915C polymorphism, no obvious associations were found for all genetic models. CONCLUSION: This meta-analysis suggests that T869C polymorphism of TGF-ß1 may be associated with RP risk only in Caucasians, and there may be no association between C509T and G915C polymorphism and RP risk.

ATM polymorphisms predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.

PURPOSE: The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). METHODS AND MATERIALS: We genotyped 3 potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [-111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive (chemo)radiation therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. RESULTS: Of 362 patients (72.4% of non-Hispanic whites), 56 (15.5%) experienced grade ≥3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29-0.83, P=.009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P=.036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P=.002). Such positive findings remained in non-Hispanic whites. CONCLUSIONS: ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.

A study of ethnic differences in TGFß1 gene polymorphisms and effects on the risk of radiation pneumonitis in non-small-cell lung cancer.

BACKGROUND: To investigate whether Chinese non-small-cell lung cancer (NSCLC) patients with risk of radiation pneumonitis (RP) (grade ≥ 3) caused by radiotherapy display reliable single-nucleotide polymorphism (SNP) marker(s) located on the transforming growth factor-beta-1 (TGFß1) gene. METHODS: DNA was isolated from blood samples obtained from NSCLC patients (n = 167) treated with radiotherapy alone (n = 23) or chemoradiation (n = 144) with the median total radiation dose of 56 Gy between 2007 and 2010. A comprehensive approach toward characterizing the TGFß1 SNPs in Chinese patients was carried out in this study. Eight SNPs of the TGFß1 gene (rs1800469, rs1800471, rs1982073, rs4803455, rs11466345, rs12983047, rs10417924, and rs10980942) were finally genotyped by the direct DNA sequencing method. Kaplan-Meier cumulative probability was used to assess the risk of RP of grade 3 or higher. Cox proportional hazard analysis was used to evaluate the effect of TGFß1 genotypes on RP risk. RESULTS: A total of 46 patients (27.5%) developed RP of grade 3 or higher, based on Common Terminology Criteria for Adverse Events version 3.0, with a median follow-up of 29.5 months (range, 16-58). The rs1982073 SNP, associated with RP risk in whites, was not found to be associated with the risk of RP of grade 3 or higher in Chinese NSCLC patients. Multivariate analysis found AG/GG genotypes of the novel TGFß1 SNP rs11466345 to be associated with a significantly higher risk of RP of grade 3 or higher compared with the AA genotypes, after adjustment for age, smoking status, and dosimetric parameters (for mean lung dose, adjusted hazards ratio = 2.295, 95% confidence interval: 1.101-4.783, p = 0.027; for volume of normal lung receiving 20 GY or more radiation, adjusted hazards ratio = 2.142, 95% confidence interval: 1.033-4.441, p = 0.041). CONCLUSION: The AG/GG genotypes of novel TGFß1 rs11466345 were associated with a higher risk of RP in Chinese NSCLC patients treated with radiotherapy. The rs1982073 SNP, associated with RP risk in whites, was not correlated with higher RP risk in the Chinese patients studied. Further studies are warranted to confirm these findings in different ethnic populations.