Whole genome tiling-resolution array CGH identifies distinct DNA amplifications under vincristine selection of ovarian cancer cells
Notice bibliographique
Résumé
4143 Not all patients respond to chemotherapy. Unresponsive cells within a heterogeneous tumor mass may clonally expand and result in tumor recurrence/progression. Gene amplification has previously been described as playing a role in conferring drug resistance. Identification of gene copy number alterations in drug-resistant cells will enhance our understanding of drug resistance mechanisms and will identify novel therapeutic targets. Objective: To generate comprehensive whole genome profiles for an ovarian carcinoma cell line (SKOV3) and its vincristine-resistant derivatives (SKVCRs) so as to identify novel genes impacting drug response. This will be accomplished through use of a Comparative Genomic Hybridization (CGH) array comprised of overlapping Bacterial Artificial Chromosomes (BACs) that span the entire human genome. Experimental Design: SKVCR cell lines were derived by growing SKOV3 cells in the presence of vincristine, with different levels of resistance obtained by serial passages of cells at increasing drug concentrations. Each SKVCR line was maintained and sub-cultured at the same drug concentration until doubling time was ≤48h. SKOV3 and SKVCRs were analyzed by tiling-set array CGH. Emerging drug resistance genomic alterations in the SKVCRs were identified by comparison against the SKOV3 genomic profile. Briefly, cell line was labelled and compared against a differentially labelled reference DNA sample by co-hybridization to the array. After imaging analysis, signal intensity ratios for each BAC clone were plotted against chromosomal location to reveal amplifications and deletions across the whole genome. DNA copy alterations were verified with fluorescence in situ hybridization. RNA was extracted from SKOV3 and all SKVCRs for gene expression analysis using reverse-transcriptase PCR and the U133 Plus 2.0 Array from Affymetrix. Gene expression data were correlated with tiling-set array CGH data to confirm their significance. Results: Alignment of whole genome array CGH profiles for SKOV3 and SKVCRs revealed distinct regional amplifications in response to drug selection and allowed the fine-mapping of DNA copy alterations at various loci. These include both previously characterized changes, such as amplification of the P-glycoprotein gene (MDR1 or ABCB1) and other ABC transporter genes, and novel DNA copy number gains and losses. Gene expression analysis demonstrated concurrent changes in expression for those genes identified by tiling-set array CGH. Conclusion: Increasing amplification and over-expression of MDR1 and other ABC transporters that drive drug resistance is observed across the SKVCRs. In addition, we identified novel genomic alterations that emerge with increasing drug selection. Functional analysis of those genes implicated by the tiling-set platform will follow.This work was supported by funds from Genome Canada/BC.
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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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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) | 0,001 | 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 ».