Genomic and transcriptomic landscape of extranodal marginal zone lymphoma
Notice bibliographique
Résumé
Abstract Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin B-cell lymphoma accounting for 7-10% of lymphoma diagnoses. Extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT) is the most common subtype (61%) of MZL. While the mutational landscape, chromosomal aberrations and transcriptome of nodal and splenic MZL have been extensively evaluated, the mutational landscape of EMZL has only been evaluated in a small number of patients and mainly by targeted sequencing. Consequently, the comprehensive genomic landscape of EMZL remains largely uncharacterized. Herein, we performed whole exome sequencing followed by targeted sequencing of potential tumor driver genes, copy number and/or RNA transcriptome analyses in 165 patients with pretreatment EMZL tumors involving 16 anatomic locations. All samples were collected and underwent expert review as part of the Atlas of Blood Cancer Genomes consortium. The most common anatomic locations were ocular adnexa (OAMZL) (n=35), gastric (n=25, including 6 positive for Helicobacter pylori), salivary glands (n=25), and lungs (n=24). Using common criteria for variant mutation calling and significant focal copy number (CN), we identified 1218 variants (1030 missense and 188 truncation mutations) across 174 genes and 2837 CN focal alterations (1614 copy gains and 1223 copy number losses). Of these genes, 44 and 11 were mutated in >5% and >10% of specimens, respectively. We detected variants identified previously by targeted sequencing in EMZL from different locations (e.g. TNFAIP3 (A20) (12%), TBL1XR1 (13%), SPEN (10%), CARD11 (7%), TET2 (7%) and CREBBP (6%)). We detected mutations in KLF2 (10 mutations in 8 EMZL patients) and PTPRD (7 mutations in 7 EMZL patients) that were previously suggested to be specific for splenic and nodal MZL, respectively. We also detected variants not previously reported in EMZL, including a transcriptional factor ZEB2, LRP1B,and others. The most frequently mutated gene in our study (25% of tumors) was IGLL5. Some mutations were limited to specific locations (e.g. ZEB2 mutations seen exclusively in gastric and salivary gland EMZL), while most were observed across all anatomic locations. There was no association between specific mutations and clonal IGHV, in contrast to previous reports. Using Enrichr tool, we observed enrichment of mutations in genes belonging to the B cell receptor activation, NOTCH signaling, Wnt-beta catenin signaling, NF-kB signaling , PI3K AKT signaling, DNA repair and other pathways. Chromosomal and copy number changes were also commonly observed including previously reported trisomy of chromosomes 3 and 18. Combining DNA mutations and CN alterations, the number of genetic lesions per tumor sample in the 174 mutated genes ranged from 0 to 95, with an average load of 17 lesions per case. RNA sequencing was successful in 159 EMZL tumors from 16 distinct anatomic locations. Unsupervised clustering using all genes with a median log2-normalized gene expression value greater than 5 and a standard deviation greater than 1 (1323 genes) demonstrated that the majority of gastric EMZL with and without H. pylori infections clustered together on 2 dendrograms as did most of the samples of OAMZL. Since the clustering could be forced by organ-specific and not tumor-specific gene expression, we next focused on the expression of the 345 genes from the LM22 matrix that passed our transcriptomic row filtering. Unsupervised clustering resulted in clustering of most gastric EMZL irrespective of H. pylori positivity together in the same dendrogram branch, accompanied by few additional EMZL from other anatomic locations. Most of the EMZL samples from other locations did not show preferential co-clustering together. On comparison of gene expression between gastric and OAMZL, there was enrichment of the B-cell receptor signaling pathway, B-cell activation, B-cell naïve and B-cell memory cells, B-cell proliferation and NF-kB signaling in the latter. Immune microenvironment analysis showed a statistically significant increase in resting mast cells and decrease in M1 macrophages in gastric EMZL and increase in regulatory T cells in salivary EMZL. The broad genomic studies reported here underscore the biological similarity of EMZL across anatomical sites with the potential exceptions of gastric EMZL (regardless of H. Pylori status). These data provide valuable genomic and transcriptomic resources to inform future diagnostic and therapeutic strategies.
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) | 0,001 | 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 ».