Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.
BACKGROUND
Small-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined radiation and chemotherapy is the standard of care; however, treatment outcomes vary. Variability in the rate at which chemotherapy agents are metabolized and in the capacity of repairing DNA damage has been hypothesized to be partly responsible for the treatment response variation. Genes in the glutathione metabolism and DNA repair pathways were tested through tag single-nucleotide polymorphisms (SNPs) to assess their association with survival in SCLC.


METHODS
Blood DNA from 248 patients with primary SCLC was genotyped for 419 tag SNPs from 49 genes in the glutathione and DNA repair pathways. Association analyses with patient survival were carried out at single-SNP, whole-gene, and haplotype levels after adjusting for age, gender, tumor stage, treatment modalities, and smoking history.


RESULTS
Among the 375 SNPs successfully genotyped, 21 SNPs, located on 11 genes, showed significant association with survival. Whole-gene analyses confirmed 3 of the 11 genes: GSS, ABCC2, and XRCC1. Haplotype analyses of these three genes identified haplotype combinations and genomic locations underlying the observed SNP associations.


CONCLUSIONS
Genetic variations in genes involved in the glutathione and DNA repair pathways are associated with SCLC survival.
Sun
Z
Z
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Chen
J
J
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Medical Oncology, The Second Affiliated Hospital, Dalian Medical University, Dalian; Department of Medical Oncology, The First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.
Aakre
J
J
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Marks
R S
RS
Department of Medical Oncology.
Garces
Y Y
YY
Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN.
Jiang
R
R
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Idowu
O
O
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA; SUNY Downstate Medical Center, Brooklyn, NY.
Cunningham
J M
JM
Genomics Shared Resource, Mayo Clinic College of Medicine, Rochester, MN, USA.
Liu
Y
Y
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Medical Oncology, The First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.
Pankratz
V S
VS
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Yang
P
P
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address: yang.ping@mayo.edu.
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D005978:Glutathione / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate; D000076105:X-ray Repair Cross Complementing Protein 1
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000715087:ABCC2 protein, human; C000619371:XRCC1 protein, human