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Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.

ABSTRACT: Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

SUBMITTER: Lopez C

PROVIDER: S-EPMC6440956 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.

López Cristina C Kleinheinz Kortine K Aukema Sietse M SM Rohde Marius M Bernhart Stephan H SH Hübschmann Daniel D Wagener Rabea R Toprak Umut H UH Raimondi Francesco F Kreuz Markus M Waszak Sebastian M SM Huang Zhiqin Z Sieverling Lina L Paramasivam Nagarajan N Seufert Julian J Sungalee Stephanie S Russell Robert B RB Russell Robert B RB Bausinger Julia J Kretzmer Helene H Ammerpohl Ole O Bergmann Anke K AK Binder Hans H Borkhardt Arndt A Brors Benedikt B Claviez Alexander A Doose Gero G Feuerbach Lars L Haake Andrea A Hansmann Martin-Leo ML Hoell Jessica J Hummel Michael M Korbel Jan O JO Lawerenz Chris C Lenze Dido D Radlwimmer Bernhard B Richter Julia J Rosenstiel Philip P Rosenwald Andreas A Schilhabel Markus B MB Stein Harald H Stilgenbauer Stephan S Stadler Peter F PF Szczepanowski Monika M Weniger Marc A MA Zapatka Marc M Eils Roland R Lichter Peter P Loeffler Markus M Möller Peter P Trümper Lorenz L Klapper Wolfram W Hoffmann Steve S Küppers Ralf R Burkhardt Birgit B Schlesner Matthias M Siebert Reiner R

Nature communications 20190329 1

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset ...[more]

PMID: 30926794

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Project description:Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Dataset Information

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.

Publications

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.

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