Abstract 2447: The mutational landscape of chemo-refractory Burkitt lymphoma
Notice bibliographique
Résumé
Abstract Background: Burkitt Lymphoma (BL) is characterized by rapid cellular proliferation driven by the canonical IG-MYC translocation. BL can evade apoptosis by silencing the tumor suppressor TP53 or by mutating MYC. Other mutations contribute to the pathogenesis of BL, including TCF3 or ID3, which stimulate PI3K/MAPK/MTOR signaling, or mutations in CCND3, which accelerate cell cycle progression. While BL is curable in 90% of patients, the prognosis for relapsed BL is dismal. The mutational landscape of relapsed BL (rBL) is not well characterized because it is rarely re-biopsied at the time of relapse. Two young men at our institution experienced a BL relapse within 3 months of completing intensive chemotherapy. We hypothesized that mutations implicated in therapeutic resistance would be enriched in the tumor cells taken at the time of relapse. Our aim was to identify these mutations and develop cell lines from these patients to study these tumours in more detail. Methods: Both patients had whole exome sequencing (WES) performed on tumor cells obtained at the time of diagnosis (T1) and relapse (T2), using unaffected peripheral blood to exclude germline variants. The novel cell lines (CL) derived from T2 were also sequenced and karyotyped. Results: The total number of coding mutations in patient 509 was: T1 = 78, T2 = 84 and CL= 63, and in patient 533: T1= 43, T2 = 66 and CL= 70. All samples had multiple missense mutations (5 to 7) in MYC and had evidence of clonal heterogeneity. Patient 509 had a TP53 (R248) mutation that was clearly selected for during chemotherapy, where the variant allele fraction (VAF) increased from 2% at T1 to 93% at T2. 19 genes had acquired missense mutations at T2 including: CD14, GSTM3, BCR and ELMO3. The following genomic rearrangements were observed in the 509CL by karyotype:-Y,t(8;14)(q24.21;q32),der(10)t(10;22)(p1?3;q11.2),t(13;17)(q3?2;q11.2), del(17)(p11.2) and -22. Patient 533 had multiple frameshift mutations that occurred in all three samples (T1, T2 and CL), including in CCND3, BAX, ARID1A, ARID1B, DDX5, DETD1B, TSFM, SP3 and TFAP4. T2 and the CL had additional acquired missense or nonsense mutations in ZFP36L2, CCL7, FAM13C and IKBKB. The 533CL had 3 dominant clones by karytope, The rearrangements observed were: del(2)(p21p23), t(8;14)(q24.21;q32) ,t(1;12)(q12;q24) and +7. The frameshift mutations in ZFP36L2 and BAX were homozygous in the 533CL. Conclusions: Multiple genes are implicated in the pathogenesis of chemotherapy-resistant BL, many of which had not been appreciated in studies focused on sequencing de novo BL (e.g. BAX, ARID1A). To our knowledge, these are the first BL cell lines that have been well-characterized with respect to the serial acquisition of mutations after exposure to chemotherapy and with knowledge of germline variants. These are useful resources to study oncogene cooperation, clonal evolution, chromatin remodelling (ARID1A), RNA processing (DDX5, ZFP36L2) and apoptosis (P53 and BAX null) in BL. Citation Format: Claudia M. Wever, Maryse Lemaire, Donald C. Vinh, Josée Hébert, Yasser Riazalhosseini, Ryan Morin, Nathalie A. Johnson. The mutational landscape of chemo-refractory Burkitt lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2447. doi:10.1158/1538-7445.AM2017-2447
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 ».