title: Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.
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.
authors: Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: X
authors: X
authors: Pu
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors: L
authors: L
authors: Wang
authors: Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: J Y
authors: JY
authors: Chang
authors: Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: M A T
authors: MA
authors: Hildebrandt
authors: Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Y
authors: Y
authors: Ye
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: C
authors: C
authors: Lu
authors: Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: H D
authors: HD
authors: Skinner
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors: N
authors: N
authors: Niu
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors: G D
authors: GD
authors: Jenkins
authors: Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: R
authors: R
authors: Komaki
authors: Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: J D
authors: JD
authors: Minna
authors: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: J A
authors: JA
authors: Roth
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors: R M
authors: RM
authors: Weinshilboum
authors: Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors: X
authors: X
authors: Wu
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000532:radiotherapy*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance; D011878:Radiotherapy / Q000009:adverse effects