{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T13:59:55Z","timestamp":1772200795399,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype\u2013toxicity association analyses were performed with R package SNPassoc. Among the results, ABCC2 c.1249A allele (rs2273697) and ABCG2 intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas ABCC2 c.3563A allele had a protective effect, as well as ABCB1 variants rs2032582 and rs1128503 (p-value &lt; 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A &gt; G) increased the risk of severe overall hepatotoxicity (p = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.<\/jats:p>","DOI":"10.3390\/cancers12123647","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T11:59:00Z","timestamp":1607083140000},"page":"3647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Maud","family":"Maillard","sequence":"first","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France"},{"name":"Universit\u00e9 Paul Sabatier\u2014Toulouse III, 31400 Toulouse, France"},{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Chevreau","sequence":"additional","affiliation":[{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3699-2729","authenticated-orcid":false,"given":"F\u00e9licien","family":"Le Louedec","sequence":"additional","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France"},{"name":"Universit\u00e9 Paul Sabatier\u2014Toulouse III, 31400 Toulouse, France"},{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manon","family":"Cassou","sequence":"additional","affiliation":[{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Delmas","sequence":"additional","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France"},{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laure","family":"Gourdain","sequence":"additional","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France"},{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7190-120X","authenticated-orcid":false,"given":"Jean-Yves","family":"Blay","sequence":"additional","affiliation":[{"name":"Medical Oncology 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France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinne","family":"Delcambre-Lair","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Centre Francois Baclesse, 14000 Caen, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5243-1548","authenticated-orcid":false,"given":"Nicolas","family":"Penel","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Centre Oscar Lambret\u2014Universit\u00e9 de Lille, 59000 Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Bertucci","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Institut Paoli-Calmettes, 13009 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9cile","family":"Guillemet","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Centre Henri Becquerel, 76038 Rouen, 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Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel","family":"Le Cesne","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Gustave Roussy, 94805 Villejuif, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9886-412X","authenticated-orcid":false,"given":"Fabienne","family":"Thomas","sequence":"additional","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France"},{"name":"Universit\u00e9 Paul Sabatier\u2014Toulouse III, 31400 Toulouse, France"},{"name":"Institut Claudius Regaud, Institut Universitaire du Cancer (IUCT)\u2014Oncopole, 31059 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13303","DOI":"10.1021\/bi960306b","article-title":"DNA Sequence- and Structure-Selective Alkylation of Guanine N2 in the DNA Minor Groove by Ecteinascidin 743, a Potent Antitumor Compound from the Caribbean Tunicate Ecteinascidia turbinata","volume":"35","author":"Pommier","year":"1996","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8155","DOI":"10.1158\/0008-5472.CAN-06-0179","article-title":"Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin","volume":"66","author":"Herrero","year":"2006","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00280-015-2918-1","article-title":"Unique features of 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