{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:06:28Z","timestamp":1789383988719,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"crossref","award":["075-15-2025-463"],"award-info":[{"award-number":["075-15-2025-463"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Pharmacogenetic testing of the dihydropyrimidine dehydrogenase gene (DPYD) is increasingly incorporated into clinical practice to identify patients at increased risk of fluoropyrimidine-related toxicity. However, most routine assays target a limited number of well-established variants, whereas the DPYD gene demonstrates substantial population variability and may harbor rare potentially functional alleles that are not detected by conventional targeted testing. Data describing coding and splice-region DPYD variants detectable by whole-exome sequencing in Russian oncology populations remain limited. This study aimed to characterize the frequency and distribution of common, clinically relevant, and rare DPYD variants in a Russian cohort of patients receiving fluoropyrimidine-containing chemotherapy and to compare the observed allele frequencies with European and East Asian reference populations. Methods: Descriptive pharmacogenetic analysis was performed in 339 patients with malignant tumors treated with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), folinic acid, fluorouracil, and oxaliplatin (FOLFOX), or folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) regimens. Whole-exome sequencing was performed using Illumina technology with exome enrichment by KAPA HyperExome and a sequencing depth of at least 100\u00d7. Sequence reads were aligned to the Genome Reference Consortium Human Build 38 (GRCh38) reference genome, germline variants were called using Genome Analysis Toolkit (GATK), HaplotypeCaller, and functional annotation was performed with Ensembl Variant Effect Predictor. DPYD variants were classified according to their population frequency, predicted functional effect, ClinVar annotations, and current pharmacogenetic recommendations. Allele and genotype frequencies were calculated and descriptively compared with Genome Aggregation Database (gnomAD) v4.1.1 Non-Finnish European and East Asian populations. Results: Seventeen DPYD variants were identified. The most frequent alternative alleles were rs1801265 (24.93%), rs1801159 (17.70%), rs2297595 (11.06%), rs1801160 (7.08%), and rs17376848 (5.16%). Their distribution was generally closer to that observed in the Non-Finnish European population than in East Asian populations. The established reduced-function variant rs67376798 (c.2846A&gt;T, p.Asp949Val) was detected in one heterozygous patient, corresponding to a carrier frequency of 0.29% and an allele frequency of 0.15%. The HapB3 proxy variant rs56038477 (c.1236G&gt;A) was identified in 13 heterozygous patients, with a carrier frequency of 3.83% and an allele frequency of 1.92%; confirmation of the functional intronic variant rs75017182 would be required for definitive HapB3 assignment. Overall, rs67376798 or rs56038477 was detected in 14 patients (4.13%). In addition, rare variants with a cohort allele frequency below 1% were identified in 11 patients (3.24%). Among these, p.Thr65Ala, p.Thr65Met, p.Asn151Asp, and p.Val691Leu represented potentially relevant findings requiring further functional validation. Conclusions: Whole-exome analysis revealed a heterogeneous spectrum of DPYD variants in the studied Russian oncology cohort, including both established pharmacogenetic markers and rare variants that would not be captured by limited targeted panels. The overall allele-frequency pattern was predominantly similar to that of European reference populations, although several rare variants demonstrated distinct distributions. These findings support the value of population-specific characterization of DPYD and suggest that expanded sequencing approaches may complement conventional pharmacogenetic testing by identifying rare potentially functional alleles.<\/jats:p>","DOI":"10.3390\/genes17091082","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:26:11Z","timestamp":1788956771000},"page":"1082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Allelic Variants of the DPYD Gene in Russian Patients with Cancer: The Results of Exome Sequencing"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-7367","authenticated-orcid":false,"given":"Denis","family":"Fedorinov","sequence":"first","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, 119991 Moscow, Russia"},{"name":"Moscow Multidisciplinary Clinical Center \u201cKommunarka\u201d, 108814 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare of the Russian Federation, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7281-3591","authenticated-orcid":false,"given":"Vladimir","family":"Lyadov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare of the Russian Federation, 125993 Moscow, Russia"},{"name":"Moscow State Budgetary Healthcare Institution \u201cOncological Center No. 1 of Moscow City Hospital Named After S.S. Yudin, Moscow Healthcare Department\u201d, 115446 Moscow, Russia"},{"name":"Novokuznetsk State Institute of Postgraduate Medical Education\u2014Branch of Russian Medical Academy of Continuous Professional Education, 654005 Novokuznetsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Marina","family":"Lyadova","sequence":"additional","affiliation":[{"name":"Moscow State Budgetary Healthcare Institution \u201cOncological Center No. 1 of Moscow City Hospital Named After S.S. Yudin, Moscow Healthcare Department\u201d, 115446 Moscow, Russia"},{"name":"Novokuznetsk State Institute of Postgraduate Medical Education\u2014Branch of Russian Medical Academy of Continuous Professional Education, 654005 Novokuznetsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-1499","authenticated-orcid":false,"given":"Sherzod","family":"Abdullaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0227-2651","authenticated-orcid":false,"given":"Ivan","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Anna","family":"Filatova","sequence":"additional","affiliation":[{"name":"E.M. Tareev Clinic of Rheumatology, Nephrology, and Occupational Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia"},{"name":"Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Lavrentii","family":"Danilov","sequence":"additional","affiliation":[{"name":"Department of Genetics and Biotechnology, Federal State Budgetary Educational Institution of Higher Education, St. Petersburg State University, 7-9 Universitetskaya Nab., 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0091-2224","authenticated-orcid":false,"given":"Oleg","family":"Glotov","sequence":"additional","affiliation":[{"name":"Federal Scientific and Clinical Center for Infectious Diseases, Federal Medical Biological Agency of Russian Federation, 9A Professora Popova Str., 197022 Saint Petersburg, Russia"},{"name":"State Budgetary Healthcare Institution \u201cMoscow Scientific and Practical Center for Laboratory Research of the Moscow Healthcare Department\u201d, 49 Orekhovy Boulevard, Bld. 1, 115580 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7277-9985","authenticated-orcid":false,"given":"Iuliia","family":"Budagova","sequence":"additional","affiliation":[{"name":"Federal Scientific and Clinical Center for Infectious Diseases, Federal Medical Biological Agency of Russian Federation, 9A Professora Popova Str., 197022 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Karin","family":"Mirzaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare of the Russian Federation, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Ministry of Healthcare of the Russian Federation, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","first-page":"1603","article-title":"Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature","volume":"14","author":"White","year":"2021","journal-title":"Pharmgenom. Pers. Med."},{"key":"ref_2","unstructured":"European Medicines Agency (EMA) (2026, May 07). EMA Recommendations on DPD Testing Prior to Treatment with Fluorouracil, Capecitabine, Tegafur and Flucytosine. Internet Document: 30 April 2020. 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Cancer"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1082\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:40:16Z","timestamp":1789382416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091082"],"URL":"https:\/\/doi.org\/10.3390\/genes17091082","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}