Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 96, Issue 5, Pages 609-615Publisher
WILEY-BLACKWELL
DOI: 10.1038/clpt.2014.154
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Funding
- US National Institutes of Health [R01-CA111646, P50CA070907, R01-CA127615, CPRIT RP130502, U19-GM61388, R01-CA138461]
- Center for Translational and Public Health Genomics of the Duncan Family Institute for Cancer Prevention and Risk Assessment, University of Texas MD Anderson Cancer Center
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Definitive radiotherapy improves Iocoregional 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-Ill 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 TNESF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.
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