Universität zu Köln

Kuenstner, Axel, Witte, Hanno M., Riedl, Joerg, Bernard, Veronica, Stoelting, Stephanie, Merz, Hartmut, Olschewski, Vito, Peter, Wolfgang, Ketzer, Julius, Busch, Yannik ORCID: 0000-0001-6261-6853, Trojok, Peter, von Bubnoff, Nikolas, Busch, Hauke, Feller, Alfred C. and Gebauer, Niklas (2022). Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing. Haematologica, 107 (8). S. 1850 - 1864. PAVIA: FERRATA STORTI FOUNDATION. ISSN 0390-6078

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuenstner, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Witte, Hanno M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedl, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Bernard, Veronica UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoelting, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Merz, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Olschewski, Vito UNSPECIFIED UNSPECIFIED UNSPECIFIED Peter, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Ketzer, Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Yannik UNSPECIFIED orcid.org/0000-0001-6261-6853 UNSPECIFIED Trojok, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bubnoff, Nikolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Hauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Feller, Alfred C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebauer, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685178
DOI:	10.3324/haematol.2021.279631
Journal or Publication Title:	Haematologica
Volume:	107
Number:	8
Page Range:	S. 1850 - 1864
Date:	2022
Publisher:	FERRATA STORTI FOUNDATION
Place of Publication:	PAVIA
ISSN:	0390-6078
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BURKITT-LYMPHOMA; SURVIVAL; CANCER; EXPRESSION; SIGNATURES; PROGNOSIS; DISTINCT; DLBCL; TOOL Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68517