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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Population-scale predictions of DPD and TPMT phenotypes using a quantitative pharmacogene-specific ensemble classifier

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Zhou, Yitian [1] ; Dagli Hernandez, Carolina [2, 1] ; Lauschke, Volker M. [1]
Total Authors: 3
[1] Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm - Sweden
[2] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo - Brazil
Total Affiliations: 2
Document type: Journal article
Source: BRITISH JOURNAL OF CANCER; v. 123, n. 12, p. 1782-1789, DEC 8 2020.
Web of Science Citations: 0

Background Inter-individual differences in dihydropyrimidine dehydrogenase (DPYDencoding DPD) and thiopurine S-methyltransferase (TPMT) activity are important predictors for fluoropyrimidine and thiopurine toxicity. While several variants in these genes are known to decrease enzyme activities, many additional genetic variations with unclear functional consequences have been identified, complicating informed clinical decision-making in the respective carriers. Methods We used a novel pharmacogenetically trained ensemble classifier to analyseDPYDandTPMTgenetic variability based on sequencing data from 138,842 individuals across eight populations. Results The algorithm accurately predicted in vivo consequences ofDPYDandTPMTvariants (accuracy 91.4% compared to 95.3% in vitro). Further analysis showed high genetic complexity of DPD deficiency, advocating for sequencing-basedDPYDprofiling, whereas genotyping of four variants inTPMTwas sufficient to explain >95% of phenotypic TPMT variability. Lastly, we provided population-scale profiles of ethnogeographic variability in DPD and TPMT phenotypes, and revealed striking interethnic differences in frequency and genetic constitution of DPD and TPMT deficiency. Conclusion These results provide the most comprehensive data set ofDPYDandTPMTvariability published to date with important implications for population-adjusted genetic profiling strategies of fluoropyrimidine and thiopurine risk factors and precision public health. (AU)

FAPESP's process: 19/19009-4 - In silico functionality prediction analysis of pharmacogenes and development of a pharmacogenetic score for Brazilian familial hypercholesterolemia patients
Grantee:Carolina Dagli Hernandez
Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)