title: A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy.
abstract: BACKGROUND
  This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.
  
  
  METHODS
  A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.
  
  
  RESULTS
  With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.
  
  
  CONCLUSIONS
  This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
authors.affiliation: Harvard Radiation Oncology Program, Boston, MA, USA.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Mak
authors.forename: Brian M
authors.initials: BM
authors.lastname: Alexander
authors.forename: Kofi
authors.initials: K
authors.lastname: Asomaning
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: Chen-yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Brian
authors.initials: B
authors.lastname: Napolitano
authors.forename: Andrzej
authors.initials: A
authors.lastname: Niemierko
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
authors.forename: Noah C
authors.initials: NC
authors.lastname: Choi
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011829:Radiation Dosage; D017564:Radiation Pneumonitis / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects* / Q000379:methods; D012306:Risk; D012307:Risk Factors
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)