Abstract 1869: Methylation signatures associated with T790M status in progressive NSCLC
Notice bibliographique
Résumé
Abstract Background: Emergence of the EGFR T790M mutation accounts for acquired first generation EGFR TKI resistance in over half of patients with EGFR mutant NSCLC. In patients without emergent T790M, resistance mechanisms are less well understood. We explored the impact of DNA methylation status and TKI treatment failure in these patients. Methods: Using a prospective cohort of patients with acquired TKI resistance, tumour tissue samples pre/post TKI exposure were identified. DNA was extracted from FFPE tissue using the Qiagen AllPrep DNA/RNA FFPE Extraction Protocol, and subsequently analyzed using the Illumina Infinium EPIC array. Raw microarray data files were processed using the software package minfi for data normalization (Illumina method) and extraction of methylation levels (M-values). Samples were split into two groups according to the T790M status of each sample (T790M + or T790M-). The set of most informative probes, those whose M-value profiles align most closely with the T790M status of the study samples, was generated by selecting the 1,000 probes with lowest ANOVA's p-value. The stability of the resulting sample clustering was assessed by hierarchical clustering (Euclidean distance), classification with internal cross-validation (SVM leave-one-out), and non-parametric dimensional reduction (t-SNE). Results: 40 samples from 36 EGFR mutant NSCLC patients were successfully profiled. Pre TKI samples were available in 10 patients with an EGFR mutation of which 4 had matched post TKI tissue (3 T790M+, 1 T790M-). The remaining 26 samples in post TKI patients included 17 T790M + and 9 T790M- cases. A DNA methylation-based signature was developed by selecting the array probes that best discriminated T790M+ from T790M- cases. Group membership was stable, as shown by cross-validation by three different methods (hierarchical clustering, SVM leave-one-out and t-SNE). The 1,000 probe cut-off was arbitrarily selected; however, identical sample clusters were obtained using 500 or 2,000 methylation array probes. When analyzing the genomic location of the set of probes that form the signature, we found broad distribution across all chromosomes, thus, ruling out the possibility of selection bias due to focal or chromosome-level aberrations. Several genes contained a higher number of the selected probes, including EGFR, whose expression levels are known to be regulated at the methylation level in certain cancer types. Cluster analysis using the 1,000-probe signature revealed a high degree of concordance between EGFR T790M and DNA methylation status. All post-TKI (n=20) T790M+ samples concentrated within epi-group 2, whereas 8/10 T790M- samples were found within epi-group 1. Of the 4 patients with matched samples, 2 had baseline samples within epi-group 2 and went on to develop EGFR T790M post TKI. Of the 2 with baseline samples within epi-group 1, one went on to develop T790M (post-TKI epigroup 2) and one did not (post-TKI epigroup 1). Conclusions: We observed a concordance between T790M status and epi-group suggesting that the development of resistance to EGFR-TKIs may be associated with distinct DNA methylation signatures. This signature may be present at baseline and predict for subsequent emergence of T790M. Citation Format: Grainne M. O'Kane, Alberto J. León, Muqdas Shabir, Jennifer H. Law, Penelope A. Bradbury, Geoff Liu, Adrian Sacher, Frances A. Shepherd, Dax Torti, Tracy L. Stockley, Ming Tsao, Trevor J. Pugh, Natasha B. Leighl. Methylation signatures associated with T790M status in progressive NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1869.
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 | 0,000 |
| 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) | 0,002 | 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 ».