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Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.

ABSTRACT: Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.

SUBMITTER: Pu X

PROVIDER: S-EPMC4206576 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Project description:Hepcidin is crucial in regulating iron metabolism, and increased serum levels were strongly linked with poor outcomes in various malignancies. Thus, we investigated if genetic variants in the BMP/Smad4/Hamp hepcidin-regulating pathway were associated with outcomes in patients receiving definitive radiotherapy for NSCLC. Subjects were 664 NSCLC patients who received ≥60 Gy radiotherapy for NSCLC retrospectively identified from a single-institution database. Potentially, functional and tagging single nucleotide polymorphisms (SNPs) of BMP2 (rs170986, rs1979855, rs1980499, rs235768, and rs3178250), BMP4 (rs17563, rs4898820, and rs762642), Smad4 (rs12456284), and Hamp (rs1882694, rs10402233, rs10421768, and rs12971321) were genotyped by TaqMan real-time polymerase chain reaction. Cox proportional hazard's analyses were used to assess potential influences of SNPs on overall survival (OS), local-regional progression-free survival (LRPFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). Nomogram of each endpoint model was developed using R project. The median patient age was 66 years. Most (488 [73.2%]) had stage III NSCLC. Age, disease stage, receipt of concurrent chemotherapy, and gross tumor volume were independent factors of OS. Hamp rs1882694 AC/CC genotypes were associated with poor OS, LRPFS, PFS, and DMFS in multivariate analyses. Besides, BMP2 rs1979855, rs3178250, and rs1980499 associated with PFS; Hamp rs10402233 and BMP2 rs1979855 associated with LRPFS; BMP2 rs3178250 associated with DMFS after adjustment for clinical factors. After adding SNPs to each model, all the likelihood ratios were increased; the nomograms were improved significantly to predict LRPFS (P < 0.001) and PFS (P < 0.001), and marginally to predict OS (P = 0.056) and DM (P = 0.057). Our nomograms incorporating significant SNPs in the BMP/Smad4/Hamp hepcidin-regulating pathway could improve the prediction of outcomes in patients given definitive radiotherapy for NSCLC. Intensified follow-ups would be recommended for patients with unfavorable outcomes identified in nomograms. Due to the rapid developments of targeted therapies and immunotherapies for NSCLC, it is necessary to further validate our findings in patients receiving such treatments.

Project description:PurposeTransforming growth factor (TGF) -β1 signaling is involved in cancer-cell metastasis. We investigated whether single nucleotide polymorphisms (SNPs) at TGFβ1 were associated with overall survival (OS) and distant metastasis-free survival (DMFS) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy, with or without chemotherapy.MethodsWe genotyped TGFβ1 SNPs at rs1800469 (C-509T), rs1800471 (G915C), and rs1982073 (T+29C) by polymerase chain reaction-restriction fragment length polymorphism in blood samples from 205 NSCLC patients who had had definitive radiotherapy at one institution in November 1998-January 2005. We also tested whether the TGF-β1 rs1982073 (T+29C) SNP affected the migration and invasion of A549 and PC9 lung cancer cells.ResultsMedian follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis). Multivariate analysis showed that the TGFβ1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P = 0.032) and that the TGFβ1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose. Transfection with TGFβ1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGFβ1+29C may be linked with increased metastatic potential.ConclusionsTGFβ1 genotypes at rs1800469 and rs1982073 could be useful for predicting DMFS among patients with NSCLC treated with definitive radiation therapy. These findings require validation in larger prospective trials and thorough mechanistic studies.

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Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.

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