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    ABSTRACT: Background: The activity of thiopurine methyltransferase (TPMT) is subject to genetic variation. Loss-of-function alleles are associated with various degrees of myelosuppression after treatment with thiopurine drugs, thus genotype-based dosing recommendations currently exist. The aim of this study was to evaluate the potential utility of leveraging genomic data from large biorepositories in the identification of individuals with TPMT defective alleles. Material and methods: TPMT variants were imputed using the 1000 Genomes Project reference panel in 87,979 samples from the biobank at The Children's Hospital of Philadelphia. Population ancestry was determined by principal component analysis using HapMap3 samples as reference. Frequencies of the TPMT imputed alleles, genotypes and the associated phenotype were determined across the different populations. A sample of 630 subjects with genotype data from Sanger sequencing (N = 59) and direct genotyping (N = 583) (12 samples overlapping in the two groups) was used to check the concordance between the imputed and observed genotypes, as well as the sensitivity, specificity and positive and negative predictive values of the imputation. Results: Two SNPs (rs1800460 and rs1142345) that represent three TPMT alleles ((*)3A, (*)3B, and (*)3C) were imputed with adequate quality. Frequency for the associated enzyme activity varied across populations and 89.36-94.58% were predicted to have normal TPMT activity, 5.3-10.31% intermediate and 0.12-0.34% poor activities. Overall, 98.88% of individuals (623/630) were correctly imputed into carrying no risk alleles (553/553), heterozygous (45/46) and homozygous (25/31). Sensitivity, specificity and predictive values of imputation were over 90% in all cases except for the sensitivity of imputing homozygous subjects that was 80.64%. Conclusion: Imputation of TPMT alleles from existing genomic data can be used as a first step in the screening of individuals at risk of developing serious adverse events secondary to thiopurine drugs.
    Frontiers in Genetics 05/2014; 5:96. DOI:10.3389/fgene.2014.00096
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    ABSTRACT: Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient's clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing.
    Pharmacogenomics and Personalized Medicine 01/2014; 7:227-40. DOI:10.2147/PGPM.S48887
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    ABSTRACT: Pharmacogenetics (PGx) is the study of the relationship between inter-individual genetic variation and drug responses. Germline variants of genes involved in drug metabolism, drug transport, and drug targets can affect individual response to medications. Cancer therapies are characterized by an intrinsically high toxicity; therefore, the application of pharmacogenetics to cancer patients is a particularly promising method for avoiding the use of inefficacious drugs and preventing the associated adverse effects. However, despite continuing efforts in this field, very few labels include information about germline genetic variants associated with drug responses. DPYD, TPMT, UGT1A1, G6PD, CYP2D6, and HLA are the sole loci for which the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) report specific information. This review highlights the germline PGx variants that have been approved to date for anticancer treatments, and also provides some insights about other germline variants with potential clinical applications. The continuous and rapid evolution of next-generation sequencing applications, together with the development of computational methods, should help to refine the implementation of personalized medicine. One day, clinicians may be able to prescribe the best treatment and the correct drug dosage based on each patient’s genotype. This approach would improve treatment efficacy, reduce toxicity, and predict non-responders, thereby decreasing chemotherapy-associated morbidity and improving health benefits.
    Cellular Oncology 01/2015; DOI:10.1007/s13402-014-0214-4 · 2.12 Impact Factor

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