Polymorphisms in Multidrug Resistance-Associated Protein Genes Are Associated with Worse Outcome in Childhood Acute Lymphoblastic Leukemia.
Notice bibliographique
Résumé
Abstract Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of childhood acute lymphoblastic leukemia (ALL). Inter-individual differences in response to this drug may cause treatment failures and adverse drug reactions. In particular, transporters of the adenosine triphosphate-binding cassette (ABC) family such as the ABCC (multidrug resistance-related protein, MRP) are involved in the efflux of this drug. The elimination of MTX may arise, among other factors, to be a major determinant of chemoresistance in leukemic blast cells. It has been demonstrated that ALL patients with high MRP expression had an unfavourable prognosis with relapsed patients showing a higher expression of MRP genes. The polymorphisms in MRP genes, particularly those in promoter region may explain differences in expression and thereby the inter-individual differences in clinical outcome for ALL children. We analyzed polymorphisms in five MRP genes (MRP1-MRP5). Two polymorphisms in MRP1, 7 in MRP2, 4 in MRP3, 8 in MRP4 and 3 in MRP5 gene, located in regulatory and coding gene regions were selected from NCBI dbSNP database. The polymorphisms were analyzed in 50 healthy individuals to estimate allele frequency, linkage disequilibrium, and haplotype phase. Variants sufficient to infer most common haplotypes were further analyzed in 243 children with de novo ALL, treated at Ste-Justine Hospital with multi-agent chemotherapy according to the Dana-Farber Cancer Institute protocols 87-01, 91-01, 95-01 and 2000-01. These polymorphisms/haplotypes were investigated for association with disease outcome. The polymorphisms of two genes, MRP1 and MRP3, appeared associated with event free survival (EFS). Individuals with the AA -genotype of A -1665G promoter polymorphism in MRP1 gene had worse EFS (69% vs. 85%, p=0.007) compared to patients with the GG or AG genotypes (Hazard ratio, HR=2.2 (IC 95%: 1.2–3.9). Carriers of A allele of G-1696A and A-189T polymorphisms in the MRP3 gene had a worse EFS (68% vs. 81%, p=0.016) compared to those with the GG or TT genotype respectively (HR=2,1 IC 95%: 1.1–3.8). The A alleles of both polymorphisms belong to the same haplotype. A-189 is uniquely tagging this haplotype, therefore the association between this haplotype and ALL outcome was also found. A-1696 is shared among this and additional haplotype, the latter not associated with EFS, rendering A-1696 allele less relevant for the prediction of ALL outcome. All associations remained significant in multivariate analysis after inclusion of the known prognostic factors. Similar results were obtained if disease free and overall survival were analyzed instead of EFS. As MRPs are also expressed in the blood-brain barrier, a possible correlation between these polymorphisms and type of relapse (isolated bone marrow or central nervous system) was analysed. No significant difference between the type of relapse and MRP1 or MRP3 described polymorphisms was seen. The variants MRP1 A-1665, and MRP3 A-189 localised in the regulatory region of these genes, have an impact on the outcome in ALL children and could predict differences in MTX response. Further analysis between these polymorphisms and MTX levels as well as combined effect with other at risk genotypes of the folate cycle should be analysed to determine the effect of MRP variants on the outcome of children with ALL.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».