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

Abstract

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. © 2008 Elsevier Ireland Ltd. All rights reserved.