A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer Entered on NCIC CTG Trial MA.27. A Pharmacogenetics Research Network-RIKEN Collaboration.
Notice bibliographique
Résumé
Abstract Background: The third-generation aromatase inhibitors (AIs) are established adjuvant therapy for postmenopausal women with early stage breast cancer. Musculoskeletal adverse events (MS AE) have become increasingly recognized as an issue for many women receiving AIs resulting in decreased quality of life and, in some instances, discontinuation of the AI. MA.27 is an ongoing randomized clinical trial comparing anastrozole with exemestane that accrued 7576 patients (pts), including 6827 from North America, about 79% of whom provided DNA and consent for genetic testing. A review of withdrawals related to adverse events revealed that the most common cause was MS AE. The hypothesis for our study was that a genome-wide association (GWA) case control study would identify single nucleotide polymorphisms (SNPs) associated with MS AE.Methods: Cases were defined as pts with grade 3 or 4 MS AE (NCI CTCAE v3.0) or who went off treatment for any grade MS AE within the first 2 years and were matched to 2 controls based on treatment arm, length of follow-up, prior chemotherapy, age and prior celecoxib (at least 3 months prior to MS AE). The study was restricted to the 94% of pts self-identified as Caucasian. Genotyping was performed with the Illumina Human610-Quad. Genotype quality control prior to analysis required call rates ≥98%. Eigenstrat analyses were performed to control for population stratification.Results: The GWA study included 293 cases and 586 controls with 6 pts (0.7%) (4 cases, 2 controls) excluded for call rates <98%. 551,358 SNPs were used in the analyses after removing 29,439 for a minor allele frequency <1% and 82 with Hardy Weinberg Equilibrium p-values <10-6. Eigenvectors did not impact the results when used as covariates. Four SNPs with the lowest p-values (3.3-8.2 x 10-6, Armitage test), 3 in high LD (r2>.8) on chromosome (ch) 14 (rs7158782, rs7159713, rs2369049) and 1 on the X ch (rs6637820) were identified. The gene closest (4000-7000 bp) to the 3 SNPs on ch 14 was T-Cell Leukemia 1A (TCL1A), encoding a protein known to augment AKT kinase activity. Expression array data from lymphoblastoid cell lines from 300 subjects of 3 ethnicities revealed that all 3 SNPs were associated with decreased TCL1A expression after adjusting for ethnicity using 2 probe sets (p=0.006 to 0.03). Electromobility shift assay (EMSA) showed that 2 of these SNPs (rs7158782, rs7159713) displayed a shift and the former SNP showed substantially less binding for variant than wild type. The gene closest to the X ch SNP was Immunoglobulin Superfamily 1 (IGSF1), but EMSA did not show a shift for this SNP.Conclusions: MS AEs represent a major impediment to optimal use of AIs in women with breast cancer and this GWA study identified SNPs on ch 14 that provide a focus for further research to identify pts at risk for, and means to ameliorate, this adverse event.(Supported in part by NIH grants U01GM61388, U01GM63173, P50CA116201 and U10CA77202) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 15.
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 | 0,002 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».