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

11 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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