Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival.
OBJECTIVE
Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment.


METHODS
Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; <or= 12 months) and long-term survivors (LTS; >or= 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs.


RESULTS
We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients >or= 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years).


CONCLUSIONS
Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.
Liu
Yanhong
Y
Departments of Epidemiology,Neuro-Oncology, and Pathology, TheUniversity of Texas MD Anderson CancerCente, Houston, TX 77030, USA. mbondy@mdanderson.org
Shete
Sanjay
S
Etzel
Carol J
CJ
Scheurer
Michael
M
Alexiou
George
G
Armstrong
Georgina
G
Tsavachidis
Spyros
S
Liang
Fu-Wen
FW
Gilbert
Mark
M
Aldape
Ken
K
Armstrong
Terri
T
Houlston
Richard
R
Hosking
Fay
F
Robertson
Lindsay
L
Xiao
Yuanyuan
Y
Wiencke
John
J
Wrensch
Margaret
M
Andersson
Ulrika
U
Melin
Beatrice S
BS
Bondy
Melissa
M
D000367:Age Factors; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics*; D016009:Chi-Square Distribution; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004260:DNA Repair; D003663:Decision Trees; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors; D013997:Time Factors; D016896:Treatment Outcome
C477345:BTBD2 protein, human; D002352:Carrier Proteins; D025743:HMGA2 Protein; C000607893:LIG4 protein, human; C532890:RTEL1 protein, human; D004265:DNA Helicases; D011088:DNA Ligases; D000072481:DNA Ligase ATP