Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia
Open Access
- 20 May 2021
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 137 (20), 2800-2816
- https://doi.org/10.1182/blood.2020005650
Abstract
The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter syndrome (RS), a rare event with dismal prognosis. In this study, we conducted whole-genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 patients recruited into a clinical trial (CHOP-O). We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumor necrosis factor receptor–associated factor 3 (TRAF3). In the noncoding genome, we discovered activation-induced cytidine deaminase–related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune-regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2, and TRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal deconvolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal-expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study. This trial was registered at www.clinicaltrials.gov as #NCT03899337.Keywords
This publication has 74 references indexed in Scilit:
- Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencingBlood, 2013
- The Life History of 21 Breast CancersCell, 2012
- Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in miceLeukemia, 2011
- Analysis of the coding genome of diffuse large B-cell lymphomaNature Genetics, 2011
- Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemiaNature, 2011
- Chronic active B-cell-receptor signalling in diffuse large B-cell lymphomaNature, 2010
- Gene set enrichment analysis made simpleStatistical Methods in Medical Research, 2009
- The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancersProceedings of the National Academy of Sciences of the United States of America, 2009
- Tumor Necrosis Factor Receptor-Associated Factor 3 Is a Critical Regulator of B Cell Homeostasis in Secondary Lymphoid OrgansImmunity, 2007
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences of the United States of America, 2003