Abstract
Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be considered in the pharmacogenomic assessment of cancer pharmacotherapy, especially in mixed populations and for drugs with a narrow safety range.
Highlights
Cancer is a leading cause of death worldwide and the total number of cases globally is increasing
Because of enzymes CYP1A1, CYP1A2, CYP2A6, CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP2D6, GSTM1, GSTT1, UGT2B7, and methylene tetrahydrofolate reductase (MTHFR) take part in the metabolism of oncological drugs (Table 1), the main goal of this study was to determine the allele frequencies of variants of these enzymes in a group representative of the Chilean population in order to describe genetic polymorphisms that might be useful in public health programs, and to compare these frequencies with other populations, as the first approximation to the evaluation of ethnic differences in the response to chemotherapies
We have studied genetic polymorphisms of several enzymes, in a sub-group of the Chilean population, which metabolize mainly antineoplastic drugs used for chemotherapy in health institutions of Chile (Table 1)
Summary
Cancer is a leading cause of death worldwide and the total number of cases globally is increasing. The number of cancer deaths is projected to increase 45% from 2007 to 2030 (from 7.9 million to 11.5 million deaths), influenced in part by an increasing and aging global population. The estimated rise takes into account expected slight declines in death rates for some cancers in high resource countries. New cases of cancer in the same period are estimated to increase from 11.3 million in 2007 to 15.5 million in 2030 (WHO, 2011). In Chile cancer have a rate of 133.7 × 100,000 inhabitants, is the second cause of death after cardiovascular diseases with a sustained increase in the time both, in the rates and in proportion of deaths.
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