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Recurrent somatic mutations in diffuse large B cell lymphoma assessed by high throughput targeted sequencing highlight molecular subtypes’ genetic divergence: a LYSA study

Abstract : Introduction: Gene expression profiling (GEP) has identified three main subtypes of diffuse large B cell lymphoma (DLBCL): germinal centre B‐cell like (GCB), activated B‐cell like (ABC) and primary mediastinal B‐cell lymphoma (PMBL). Although next generation sequencing (NGS) has enabled a more detailed genomic characterization of DLBCL, the mutation patterns observed in different studies have been heterogeneous, highlighting the need for a consensus gene panel. Furthermore, the prognostic value of these mutations has yet to be evaluated in prospective clinical trials. Methods: A Lymphopanel designed to identify mutations in 34 genes important for lymphomagenesis was used to sequence tumour DNA of 216 patients with de novo DLBCL in prospective, multicentric and randomized LNH‐03B clinical trials led by the Groupe d'Etude du Lymphome Adulte (GELA), using the Ion PGM™ system. GEP identified 81 GCB, 81 ABC, 32 unclassified and 22 PMBL samples. Results: The Lymphopanel was informative for 96% of patients: 13975 variants were identified with a median sequencing depth of 225x, and 1075 (7.7%) were validated after filtering for variant quality, SNPs and functional relevance. The mean mutation rate per megabase was 56.7, and PMBL subtype was significantly more mutated than the other subtypes (p = 7.4 × 10e−5). We confirmed that the ABC subtype is dominated by NFkB pathway mutations (46% of variants), the GCB subtype is dominated by epigenetic pathway mutations (34% of variants) and the PMBL subtype is frequently mutated in JAK‐STAT and immunity pathways (respectively 27% and 22% of variants). The Lymphopanel confirmed subtype‐enriched mutations such as MYD88, PIM1, CD79B and IRF4 variants among ABC, BCL2, CREBBP, EZH2, MEF2B and TNFRSF14 variants among GCB and SOCS1, STAT6 and TNFAIP3 variants among PMBL. The immunity pathway seems to play a crucial role in PMBL, with respectively 59%, 36% and 45% of patients presenting mutations in B2M, CD58 and CIITA. These mutations mostly lead to truncated proteins, suggesting a predilection for immune system escape in PMBL. ITPKB, MFHAS1 and XPO1 mutations, whose roles in lymphomagenesis are unclear, were heavily weighted toward PMBL and presented mutations in respectively 40.9%, 27.3% and 31.8% of PMBL patients. XPO1 mutations especially were almost exclusively PMBL specific. Furthermore, clinical correlations were found for certain gene mutations among the total cohort, notably with age (B2M, CD79B, CIITA, KMT2D, MYD88, SOCS1, STAT6, ITPKB and XPO1), Ann Arbor stage (B2M) and IPI (B2M and STAT6). TNFAIP3 mutations in ABC patients were associated with a less favourable OS (FDR < 10e − 3) and PFS (FDR = 0.014). Conclusion: This large, prospective study demonstrates the contribution of NGS with a consensus gene panel to the goal of precision therapy in DLBCL, enabling the identification of recurrent mutations with clinical, therapeutic and prognostic impact.
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Submitted on : Tuesday, February 18, 2020 - 4:48:54 PM
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  • HAL Id : hal-02483464, version 1


Sydney Dubois, Pierre Julien Viailly, Sylvain Mareschal, Philippe Bertrand, Elodie Bohers, et al.. Recurrent somatic mutations in diffuse large B cell lymphoma assessed by high throughput targeted sequencing highlight molecular subtypes’ genetic divergence: a LYSA study. 13th International Conference on Malignant Lymphoma, Jun 2015, Lugano, Switzerland. ⟨hal-02483464⟩



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