TY - JOUR
T1 - MiRNA-related genetic variations associated with radiotherapy-induced toxicities in patients with locally advanced non-small cell lung cancer
AU - Li, Rong
AU - Pu, Xia
AU - Chang, Joe Y.
AU - Ye, Yuanqing
AU - Komaki, Ritsuko
AU - Minna, John D.
AU - Roth, Jack A.
AU - Han, Baohui
AU - Wu, Xifeng
N1 - Publisher Copyright:
© 2016 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original author and source are credited.
PY - 2016/3
Y1 - 2016/3
N2 - Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis and pneumonitis, respectively. After multiple comparison correction, RPS6KB2:rs10274, SMO:rs1061280, SMO: rs1061285 remained significantly associated with esophagitis, while processing gene DGCR8:rs720014, DGCR8:rs3757, DGCR8:rs1633445 remained significantly associated with pneumonitis. Patients with the AA genotype of RPS6KB2:rs10274 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.51, p = 0.001, q = 0.06). Patients with the AG+GG genotype of SMO:rs1061280 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.53, p = 0.001, q = 0.06). Patients with the GG+GA genotype of DGCR8:rs720014 had a 3.54-fold increased risk of pneumonitis (OR: 3.54, 95% CI: 1.65-7.61, p<0.05, q <0.1). Significantly cumulative effects of the top SNPs were observed for both toxicities (P-trend <0.001). Using bioinformatics tools, we found that the genotype of rs10274 was associated with altered expression of the RPS6KB2 gene. Genebased analysis showed DGCR8 (p = 0.010) and GEMIN4 (p = 0.039) were the top genes associated with the risk of developing pneumonitis. Our results provide strong evidence that microRNA-related genetic variations contribute to the development of radiotherapy-induced acute esophagitis and pneumonitis and could thus serve as biomarkers to help accurately predict radiotherapy-induced toxicity in NSCLC patients.
AB - Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis and pneumonitis, respectively. After multiple comparison correction, RPS6KB2:rs10274, SMO:rs1061280, SMO: rs1061285 remained significantly associated with esophagitis, while processing gene DGCR8:rs720014, DGCR8:rs3757, DGCR8:rs1633445 remained significantly associated with pneumonitis. Patients with the AA genotype of RPS6KB2:rs10274 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.51, p = 0.001, q = 0.06). Patients with the AG+GG genotype of SMO:rs1061280 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07-0.53, p = 0.001, q = 0.06). Patients with the GG+GA genotype of DGCR8:rs720014 had a 3.54-fold increased risk of pneumonitis (OR: 3.54, 95% CI: 1.65-7.61, p<0.05, q <0.1). Significantly cumulative effects of the top SNPs were observed for both toxicities (P-trend <0.001). Using bioinformatics tools, we found that the genotype of rs10274 was associated with altered expression of the RPS6KB2 gene. Genebased analysis showed DGCR8 (p = 0.010) and GEMIN4 (p = 0.039) were the top genes associated with the risk of developing pneumonitis. Our results provide strong evidence that microRNA-related genetic variations contribute to the development of radiotherapy-induced acute esophagitis and pneumonitis and could thus serve as biomarkers to help accurately predict radiotherapy-induced toxicity in NSCLC patients.
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U2 - 10.1371/journal.pone.0150467
DO - 10.1371/journal.pone.0150467
M3 - Article
C2 - 26991123
AN - SCOPUS:84962169558
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 3
M1 - e0150467
ER -