Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.
BACKGROUND
LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumourigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy.


METHODS
We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A) and LIN28B (rs314280 G>A, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio(chemo)therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders.


RESULTS
Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ⩾3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR=2.97 and 2.23, 95% confidence interval (CI)=1.32-6.72 and 1.01-4.94, P=0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR=2.30 and 2.00, 95% CI=1.24-4.28 and 1.11-3.62, and P=0.008 and 0.022, respectively). Further stratified analyses showed a more consistent and profound risk in the subgroups of age <65years, males, stage III/IV, ever smokers, having radio-chemotherapy and mean lung dose (MLD) ⩾19.0Gy.


CONCLUSIONS
Genetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings.
Department of Radiation Oncology, Navy General Hospital, Beijing, China; Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Juyi
J
Wen
Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Hongliang
H
Liu
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Qiming
Q
Wang
Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Zhensheng
Z
Liu
Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Yangkai
Y
Li
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Huihua
H
Xiong
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Ting
T
Xu
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Peng
P
Li
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Li-E
LE
Wang
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Daniel R
DR
Gomez
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Radhe
R
Mohan
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Ritsuko
R
Komaki
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: zliao@mdanderson.org.
Zhongxing
Z
Liao
Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: qingyi.wei@duke.edu.
Qingyi
Q
Wei
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D059248:Chemoradiotherapy / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D016013:Likelihood Functions; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016601:RNA-Binding Proteins / Q000235:genetics*; D011829:Radiation Dosage; D017564:Radiation Pneumonitis / Q000175:diagnosis / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
C516326:LIN28B protein, human; D016601:RNA-Binding Proteins
Hazards ratio; Inflammation; LIN28; Non-small cell lung cancer; Polymorphisms; Radiation pneumonitis