Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non-Small Cell Lung Cancer after Definitive Radiotherapy

J Thorac Oncol. 2018 May;13(5):660-675. doi: 10.1016/j.jtho.2018.01.028. Epub 2018 Feb 15.


Introduction: Autophagy not only plays an important role in the progression of cancer but is also involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with NSCLC after definitive radiotherapy.

Methods: We genotyped nine potentially functional single-nucleotide polymorphisms (SNPs) in four autophagy-related genes (autophagy related 2B gene [ATG2B], autophagy related 10 gene [ATG10], autophagy related 12 gene [ATG12], and autophagy related 16 like 2 gene [ATG16L2]) in 393 North American patients with NSCLC treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in multivariable Cox proportional hazard regression analyses.

Results: We found that patients with the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS, and OS (adjusted hazard ratio = 0.59, 0.64, and 0.64; 95% confidence interval: 0.45-0.79, 0.48-0.84, and 0.48-0.86; p = 0.0004, 0.002, and 0.003, respectively), but a greater risk for development of severe RP (adjusted hazard ratio = 1.80, 95% confidence interval: 1.04-3.12, p = 0.037) than did patients with AA/AC genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated expression of the ATG16L2 gene.

Conclusion: This is the first report that one potentially functional SNP rs10898880 in ATG16L2 may be a predictor of RP, LRFS, PFS, and OS in patients with NSCLC after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.

Keywords: Autophagy pathway; Cox regression; Non–small cell lung cancer; Radiation pneumonitis; Single-nucleotide polymorphisms; Survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Autophagy-Related Proteins / genetics*
  • Autophagy-Related Proteins / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / radiotherapy*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / radiotherapy*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide
  • Radiation Pneumonitis / etiology
  • Radiation Pneumonitis / genetics*
  • Radiation Pneumonitis / pathology


  • ATG16L1 protein, human
  • Autophagy-Related Proteins