Pharmacogenetic Study of Trabectedin-Induced ...
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Article dans une revue scientifique: Article original
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Title :
Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma.
Author(s) :
Maillard, Maud [Auteur]
Centre de Physiopathologie de Toulouse-Purpan [INSERM U563 - CNRS UMR1037]
Chevreau, Christine [Auteur]
Institut Claudius Regaud [ICR]
Le Louedec, Félicien [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Cassou, Manon [Auteur]
Institut Claudius Regaud [ICR]
Delmas, Caroline [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Gourdain, Laure [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Blay, Jean-Yves [Auteur]
Centre Léon Bérard [Lyon]
Cupissol, Didier [Auteur]
UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle [ICM]
Bompas, Emmanuelle [Auteur]
Institut de Cancérologie de l'Ouest [Angers/Nantes] [UNICANCER/ICO]
Italiano, Antoine [Auteur]
Institut Bergonié [Bordeaux]
Isambert, Nicolas [Auteur]
Département d'oncologie médicale [Centre Georges-François Leclerc]
Delcambre-Lair, Corinne [Auteur]
Centre Régional de Lutte contre le Cancer François Baclesse [Caen] [UNICANCER/CRLC]
Penel, Nicolas [Auteur]
METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694
Bertucci, François [Auteur]
Cancérologie [Inserm U599/IPC]
Guillemet, Cécile [Auteur]
Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen [CLCC Henri Becquerel]
Plenecassagnes, Julien [Auteur]
Institut Claudius Regaud [ICR]
Foulon, Stéphanie [Auteur]
Centre de recherche en épidémiologie et santé des populations [CESP]
Chatelut, Étienne [Auteur]
Institut Claudius Regaud [ICR]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Le Cesne, Axel [Auteur]
Institut Gustave Roussy [IGR]
Thomas, Fabienne [Auteur]
Institut Claudius Regaud [ICR]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Centre de Physiopathologie de Toulouse-Purpan [INSERM U563 - CNRS UMR1037]
Chevreau, Christine [Auteur]
Institut Claudius Regaud [ICR]
Le Louedec, Félicien [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Cassou, Manon [Auteur]
Institut Claudius Regaud [ICR]
Delmas, Caroline [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Gourdain, Laure [Auteur]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Blay, Jean-Yves [Auteur]
Centre Léon Bérard [Lyon]
Cupissol, Didier [Auteur]
UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle [ICM]
Bompas, Emmanuelle [Auteur]
Institut de Cancérologie de l'Ouest [Angers/Nantes] [UNICANCER/ICO]
Italiano, Antoine [Auteur]
Institut Bergonié [Bordeaux]
Isambert, Nicolas [Auteur]
Département d'oncologie médicale [Centre Georges-François Leclerc]
Delcambre-Lair, Corinne [Auteur]
Centre Régional de Lutte contre le Cancer François Baclesse [Caen] [UNICANCER/CRLC]
Penel, Nicolas [Auteur]

METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694
Bertucci, François [Auteur]
Cancérologie [Inserm U599/IPC]
Guillemet, Cécile [Auteur]
Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen [CLCC Henri Becquerel]
Plenecassagnes, Julien [Auteur]
Institut Claudius Regaud [ICR]
Foulon, Stéphanie [Auteur]
Centre de recherche en épidémiologie et santé des populations [CESP]
Chatelut, Étienne [Auteur]
Institut Claudius Regaud [ICR]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Le Cesne, Axel [Auteur]
Institut Gustave Roussy [IGR]
Thomas, Fabienne [Auteur]
Institut Claudius Regaud [ICR]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Journal title :
Cancers
Abbreviated title :
Cancers (Basel)
Volume number :
12
Pages :
3647
Publication date :
2020-12-17
ISSN :
2072-6694
English keyword(s) :
ABC transporters
advanced soft tissue sarcoma
CYP450
hepatotoxicity
next-generation sequencing
pharmacogenetic
trabectedin
advanced soft tissue sarcoma
CYP450
hepatotoxicity
next-generation sequencing
pharmacogenetic
trabectedin
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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–toxicity 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 < 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A > 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.Show less >
Show more >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–toxicity 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 < 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A > 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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CHU Lille
CHU Lille
Submission date :
2023-11-15T07:40:29Z
2023-12-18T10:56:06Z
2023-12-18T10:56:06Z
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