Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients.

OBJECTIVE Pharmacogenetics suggests variants of genes involved in gemcitabine pharmacology could be useful markers for predicting inter-ethnic and inter-patient outcomes from treatment with the agent. Here, we have characterized the distribution of variants of genes involved in gemcitabine pharmacology in ethnic Asian populations and their association with non-small cell lung cancer (NSCLC) patient outcome. METHODS All genes involved in gemcitabine transport, metabolism and activity were screened for suitable variants for analysis using publications and public databases. By pyrosequencing, the frequency of qualifying variants was characterized from germline DNA of 94 healthy Asian donors and 53 NSCLC patients receiving gemcitabine-based chemotherapy. RESULTS Significant differences in genotype distribution between Caucasians and Asians were seen at 10/25 (45%) variant loci. In NSCLC patients, CDA+435 C>T variants were associated with response (p=0.026) and time to progression (p=0.016) and SLC28A1+1561 G>A variants were associated with neutropenia (p=0.030) and thrombocytopenia nadir (p=0.037). CONCLUSIONS Many genotypes in gemcitabine pharmacology vary in their frequency between Caucasians and Asians. CDA+435, and SLC28A1+1561 are worthy of further investigation as potential indicators of patient outcome after gemcitabine treatment.

[1]  C. Ulrich,et al.  Cancer pharmacogenetics: polymorphisms, pathways and beyond , 2003, Nature Reviews Cancer.

[2]  M. Taron,et al.  Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  G. Hillerdal,et al.  Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  F. Cappuzzo,et al.  Role of gemcitabine in cancer therapy. , 2005, Future oncology.

[5]  H. Ueno,et al.  Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Honghao Zhou,et al.  Ethnic Differences in Drug Disposition and Responsiveness , 1991, Clinical pharmacokinetics.

[7]  W. Gregory,et al.  Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[9]  H. McLeod,et al.  Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway , 2004, The Pharmacogenomics Journal.

[10]  Joanne Wang,et al.  (Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) Mammalian Nucleoside Transporters , 2004 .

[11]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[12]  K. Naito,et al.  Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy , 2006, British Journal of Cancer.

[13]  J. Mackey,et al.  Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. , 1999, Journal of the National Cancer Institute.

[14]  S. Groshen,et al.  Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab , 2006, Pharmacogenetics and genomics.

[15]  W. Plunkett,et al.  Preclinical characteristics of gemcitabine , 1995, Anti-cancer drugs.

[16]  Howard L McLeod,et al.  Pharmacogenomics--drug disposition, drug targets, and side effects. , 2003, The New England journal of medicine.

[17]  G. Peters,et al.  Cross-resistance of the gemcitabine resistant human ovarian cancer cell line AG6000 to standard and investigational drugs. , 1998, Advances in experimental medicine and biology.

[18]  L. Bertilsson,et al.  CYP2C19 genotype and phenotype determined by omeprazole in a Korean population. , 1996, Pharmacogenetics.

[19]  S. Groshen,et al.  A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer , 2004, British Journal of Cancer.

[20]  Conrad C. Huang,et al.  Genetic analysis and functional characterization of polymorphisms in the human concentrative nucleoside transporter, CNT2 , 2005, Pharmacogenetics and genomics.

[21]  B. Goh,et al.  Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population , 2006, Clinical pharmacology and therapeutics.

[22]  Y Z Xu,et al.  Cellular elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-potentiation. , 1992, Cancer research.

[23]  H. Ueno,et al.  Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus Cisplatin , 2005, Clinical Cancer Research.

[24]  V. Heinemann,et al.  Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. , 1988, Cancer research.

[25]  Conrad C. Huang,et al.  Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations. , 2004, Molecular pharmacology.

[26]  H. Groen,et al.  Genetic factors influencing Pyrimidine-antagonist chemotherapy , 2005, The Pharmacogenomics Journal.

[27]  R. Diasio,et al.  Advances and challenges in fluoropyrimidine pharmacogenomics and pharmacogenetics. , 2005, Pharmacogenomics.

[28]  G. Bepler,et al.  Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. , 2005, Lung cancer.

[29]  R. Hitt,et al.  DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  G. Watanabe,et al.  Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. , 2003, Cancer research.

[31]  Y Z Xu,et al.  Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. , 1990, Molecular pharmacology.

[32]  Li Wan Po,et al.  Pharmacogenetics and psychopharmacotherapy , 2000, Journal of clinical pharmacy and therapeutics.