Genetic variation in glutathione metabolism and DNA repair genes ...

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May 3, 2010 - Whole-gene analyses confirmed 3 of the 11 genes: GSS, ABCC2, and XRCC1. Haplotype analyses of these three genes identified haplotype ...

original article

Annals of Oncology 21: 2011–2016, 2010 doi:10.1093/annonc/mdq212 Published online 3 May 2010

Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients Z. Sun1, J. Chen1,2,3, J. Aakre1, R. S. Marks4, Y. Y. Garces5, R. Jiang1, O. Idowu1,6, J. M. Cunningham7, Y. Liu1,3, V. S. Pankratz1 & P. Yang1* 1

Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Department of Medical Oncology, The Second Affiliated Hospital, Dalian Medical University, Dalian; 3Department of Medical Oncology, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; Departments of 4Medical Oncology and 5Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN; 6SUNY Downstate Medical Center, Brooklyn, NY; 7 Genomics Shared Resource, Mayo Clinic College of Medicine, Rochester, MN, USA

Received 5 January 2010; revised 1 March 2010; accepted 3 March 2010

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. Patients and 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. Conclusion: Genetic variations in genes involved in the glutathione and DNA repair pathways are associated with SCLC survival. Key words: DNA repair, glutathione, polymorphism, small-cell lung cancer, survival

introduction Small-cell lung cancer (SCLC) is the most aggressive cell type among lung cancer subtypes; median survival following diagnosis is estimated to be 8–20 months [1, 2]. Virtually all patients with SCLC are treated with chemotherapy and/or radiation therapy; platinum-containing compounds (cisplatin and carboplatin) are most commonly used, and patient survival varies substantially. Platinum chemotherapeutic compounds exert their cytotoxic effects by covalently binding DNA purine bases and forming adducts, and when in cells, these compounds go through various biological transformation processes for either detoxification or excretion. Two pathways involved in platinum-based drug metabolism and treatment efficacy are phase II drug conjugation by glutathione and DNA repair system. The glutathione pathway *Correspondence to: Dr P. Yang, Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-266-5369; Fax: +1-507-266-2478; E-mail: [email protected]

includes enzymes responsible for glutathione synthesis, redox, glutathione conjugation, and transportation that remove glutathione conjugates from cells as reviewed previously [3]. High activity of the glutathione pathway may accelerate the excretion and reduce the concentration of platinum agents in cells. Deletion or single-nucleotide polymorphisms (SNPs) of genes in this pathway have been linked to varied clinical outcomes in non-small-cell lung cancer (NSCLC) [4–10]. Furthermore, the cytotoxic effect of platinum compounds on a DNA molecule can be reversed by the DNA repair mechanism consisting of several pathways and a network of many proteins. Nucleotide excision repair (NER) is one of the main mechanisms responsible for drug resistance by increased platinum-DNA adduct removal, and high levels of ERCC1 or XPD activity, for example, are associated with resistance to platinum compounds and patient survival [11, 12]. Although many studies have demonstrated significant genetic associations between genomic variations of the genes participating in the metabolism of platinum-based drugs and

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

original article

Background: Small-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined

original article repair of damaged DNA and clinical outcomes in NSCLC and other cancers [3,13–16], knowledge on SCLC is very scarce and obtained from a small number of cases. Furthermore, most studies have focused on limited candidate SNPs from a few selected genes where an effect from other genes in the same pathway or other loci on a same gene cannot be evaluated. In this study, we genotyped 248 cases of SCLC, the largest so far reported in the literature, on all genes involved in the glutathione metabolism and key genes in the DNA repair by tag SNPs to detect and characterize the potential effects of each gene’s variations in the two pathways on survival.

patients and methods subjects The participants in the study were SCLC patients, diagnosed at Mayo Clinic from 1997 to 2007 who consented to the research protocol as approved by institutional review board and donated their blood. Detailed description of identification, enrollment, blood collection, and follow-up has been provided previously [17, 18]. Briefly, each case was identified through the Mayo Clinic pathologic diagnostic system, their medical records were abstracted, and blood samples were collected. Tumor stage was defined as limited stage (involving one lung or with lymph node involvement on the same side of the chest) and extensive stage, where cancer had spread to the other lung, to lymph nodes on the other side of the chest, or to distant organs. Smoking information was obtained from medical record abstraction, questionnaires, and/or patient interviews. Pack-years were calculated by multiplying the number of packs per day by the total years of smoking. Never smokers were defined as having had smoked 500 kb apart; excluded individuals with >50% missing genotypes; excluded SNPs with Hardy–Weinberg P values of

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