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

X. Pu, L. Wang, J. Y. Chang, M. A.T. Hildebrandt, Y. Ye, C. Lu, H. D. Skinner, N. Niu, G. D. Jenkins, R. Komaki, J. D. Minna, J. A. Roth, R. M. Weinshilboum, X. Wu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)609-615
Number of pages7
JournalClinical pharmacology and therapeutics
Volume96
Issue number5
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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