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Inflammation‐Related Genetic Variants Predict Toxicity Following Definitive Radiotherapy for Lung Cancer
Author(s) -
Pu X,
Wang L,
Chang J Y,
Hildebrandt M A T,
Ye Y,
Lu C,
Skinner H D,
Niu N,
Jenkins G D,
Komaki R,
Minna J D,
Roth J A,
Weinshilboum R M,
Wu X
Publication year - 2014
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2014.154
Subject(s) - single nucleotide polymorphism , lung cancer , medicine , radiation therapy , oncology , esophagitis , genetic predisposition , expression quantitative trait loci , pneumonitis , bioinformatics , biology , lung , genotype , genetics , gene , disease , reflux
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. Clinical Pharmacology & Therapeutics (2014); 96 5, 609–615. doi: 10.1038/clpt.2014.154