Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer

Michelle A T Hildebrandt, Ritsuko Komaki, Zhongxing Liao, Jian Gu, Joe Y. Chang, Yuanqing Ye, Charles Lu, David J. Stewart, John D. Minna, Jack A. Roth, Scott M. Lippman, James D. Cox, Waun Ki Hong, Margaret R. Spitz, Xifeng Wu

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Abstract

Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10-3.39), rs5275 (HR:1.58, 95% CI:1.09-2.27), and rs689470 (HR:3.38, 95% CI:1.09-10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31-0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14-7.63 and HR:3.23, 95% CI:1.03-10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P,0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events. 2010 Hildebrandt et al.

Original languageEnglish (US)
Article numbere12402
JournalPLoS One
Volume5
Issue number8
DOIs
StatePublished - 2010

Fingerprint

lung neoplasms
Non-Small Cell Lung Carcinoma
Toxicity
Genes
inflammation
Cells
Radiation
toxicity
Inflammation
Polymorphism
genes
pneumonia
cells
Pneumonia
single nucleotide polymorphism
esophageal diseases
Single Nucleotide Polymorphism
Therapeutics
Nucleotides
Esophagitis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. / Hildebrandt, Michelle A T; Komaki, Ritsuko; Liao, Zhongxing; Gu, Jian; Chang, Joe Y.; Ye, Yuanqing; Lu, Charles; Stewart, David J.; Minna, John D.; Roth, Jack A.; Lippman, Scott M.; Cox, James D.; Hong, Waun Ki; Spitz, Margaret R.; Wu, Xifeng.

In: PLoS One, Vol. 5, No. 8, e12402, 2010.

Research output: Contribution to journalArticle

Hildebrandt, MAT, Komaki, R, Liao, Z, Gu, J, Chang, JY, Ye, Y, Lu, C, Stewart, DJ, Minna, JD, Roth, JA, Lippman, SM, Cox, JD, Hong, WK, Spitz, MR & Wu, X 2010, 'Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer', PLoS One, vol. 5, no. 8, e12402. https://doi.org/10.1371/journal.pone.0012402
Hildebrandt, Michelle A T ; Komaki, Ritsuko ; Liao, Zhongxing ; Gu, Jian ; Chang, Joe Y. ; Ye, Yuanqing ; Lu, Charles ; Stewart, David J. ; Minna, John D. ; Roth, Jack A. ; Lippman, Scott M. ; Cox, James D. ; Hong, Waun Ki ; Spitz, Margaret R. ; Wu, Xifeng. / Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. In: PLoS One. 2010 ; Vol. 5, No. 8.
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abstract = "Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95{\%} CI:1.10-3.39), rs5275 (HR:1.58, 95{\%} CI:1.09-2.27), and rs689470 (HR:3.38, 95{\%} CI:1.09-10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45{\%} reduction in pneumonitis risk (HR:0.55, 95{\%} CI:0.31-0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95{\%} CI:1.14-7.63 and HR:3.23, 95{\%} CI:1.03-10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P,0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events. 2010 Hildebrandt et al.",
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AU - Gu, Jian

AU - Chang, Joe Y.

AU - Ye, Yuanqing

AU - Lu, Charles

AU - Stewart, David J.

AU - Minna, John D.

AU - Roth, Jack A.

AU - Lippman, Scott M.

AU - Cox, James D.

AU - Hong, Waun Ki

AU - Spitz, Margaret R.

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