CRYPTIC <i>MYC</i> AND <i>BCL2</i> REARRANGEMENTS ARE AMONG A RANGE OF GENETIC MECHANISMS UNDERLYING THE DOUBLE HIT SIGNATURE IN NON‐DOUBLE HIT DIFFUSE LARGE B‐CELL LYMPHOMA
Notice bibliographique
Résumé
Introduction: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has poor outcome after standard therapy. We recently described a gene expression signature (DHITsig) that was characteristic for HGBL-DH/TH with BCL2 rearrangement (Ennishi et al. J Clin Oncol 2019). Interestingly, while this signature identified 27% of GCB diffuse large B-cell lymphoma (DLBCL) as DHITsig positive, only half of these tumors harbored both MYC and BCL2 rearrangements detected by FISH. Here, through whole genome sequencing (WGS), we sought to identify potential mechanisms for expression of DHITsig, including aberrant MYC and BCL2 expression, in non-HGBL-DH/TH-BCL2 tumors. Methods: We performed WGS on 20 DHITsig-pos tumors from Ennishi et al that lack rearrangements of MYC, BCL2, or both. Of these, 18 cases lack a matched normal and were analyzed for somatic SNVs and indels using a combination of Strelka2 and Mutect2, using the GnomAD database to filter germline variants based on population allele fraction. Structural variants and copy number alterations were identified using Manta and Control-FREEC, respectively. Results: Our analysis identified MYC or BCL2 rearrangements that were cryptic to breakapart FISH assays, revealing that 40% of these apparently non-HGBL-DH/TH-BCL2 tumors had, in fact, a “genetic double hit” (Figure 1). These MYC rearrangements involved recurrent non-IG partner loci ZCCHC7, RFTN1, or CD96. Although the breakpoints for two of these translocations were outside of the locus interrogated by FISH, the remainder involved small insertions of either the MYC gene or enhancer regions. Three tumors had focal copy number gains of MYC, including one with a double minute, and six tumors harbored gains of MIR-17-HG, a regulator of MYC expression. Similarly, rearrangements involving BCL2 that were cryptic to breakapart FISH were identified in three tumors, including the insertion of an IGK enhancer element into the BCL2 locus. In the only case lacking both BCL2 and MYC translocations, the 11q alteration associated with MYC-negative high-grade lymphomas was found. Finally, several focal deletions were found affecting the promoter region around TSS1 of the lncRNA PVT1 gene, telomeric of MYC. This locus has recently been found to contain a boundary element that insulates MYC from the actions of downstream enhancers. Keywords: diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6. Disclosures: Scott, D: Research Funding: Receives research funds from NanoString Technologies; Other Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL. Morin, R: Other Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».