Inflammation-Related Genetic Variants Predict Toxicity Following Definitive Radiotherapy for Lung Cancer

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 inflamma...

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Published in:Clinical pharmacology and therapeutics 2014-11, Vol.96 (5), p.609-615
Main Authors: 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
Format: Article
Language:English
Subjects:
Aged
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - radiotherapy
Female
Genetic Variation
Humans
Inflammation - complications
Inflammation - genetics
Lung Neoplasms - genetics
Lung Neoplasms - radiotherapy
Male
Middle Aged
Polymorphism, Single Nucleotide
Radiation Tolerance
Radiotherapy - adverse effects
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Summary: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
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2014.154