Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

被引：32

作者：

Kuenstner, Axel ^{[1
,2
,3
]}

Witte, Hanno M. ^{[4
,5
]}

Riedl, Joerg ^{[4
,6
]}

Bernard, Veronica ^{[6
]}

Stoelting, Stephanie ^{[6
]}

Merz, Hartmut ^{[6
]}

Olschewski, Vito ^{[4
]}

Peter, Wolfgang ^{[7
,8
,9
]}

Ketzer, Julius ^{[10
]}

Busch, Yannik ^{[7
]}

Trojok, Peter ^{[7
]}

von Bubnoff, Nikolas ^{[3
,4
]}

Busch, Hauke ^{[1
,2
,3
]}

Feller, Alfred C. ^{[6
]}

Gebauer, Niklas ^{[3
,4
]}

机构：

[1] Univ Lubeck, Med Syst Biol Grp, Lubeck, Germany

[2] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany

[3] Univ Hosp Schleswig Holstein, Univ Canc Ctr Schleswig Holstein, Campus Lubeck, Lubeck, Germany

[4] Univ Hosp Schleswig Holstein, Dept Hematol & Oncol, Campus Lubeck, Lubeck, Germany

[5] Fed Armed Forces Hosp Ulm, Dept Hematol & Oncol, Ulm, Germany

[6] Reference Ctr Lymph Node Pathol & Hematopathol, Hamatopathol Lubeck, Lubeck, Germany

[7] Stefan Morsch Fdn, HLA Typing Lab, Birkenfeld, Germany

[8] Univ Cologne, Fac Med, Cologne, Germany

[9] Univ Hosp Cologne, Inst Transfus Med, Cologne, Germany

[10] Univ Hosp Schleswig Holstein, Dept Pediat, Campus Lubeck, Lubeck, Germany

来源：

HAEMATOLOGICA | 2022年 / 107卷 / 08期

关键词：

BURKITT-LYMPHOMA; SURVIVAL; CANCER; EXPRESSION; SIGNATURES; PROGNOSIS; DISTINCT; DLBCL; TOOL;

D O I：

10.3324/haematol.2021.279631

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBLDH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBLDH/TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NF.B signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6rearranged HGBL.

引用

页码：1850 / 1863

页数：14

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