Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

“…This hotspot mutation has been recurrently reported in mantle cell lymphoma 35 and in pediatric BCP-ALL 36,37 and results in cellular transformation. 36 The emergence of a clone carrying the WHSC1 E1099K mutation may have been sufficient to induce early relapse in this patient.…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…3). BIRC3 inactivating mutations have been described in CLL, SMZL [91] and MCL [92,93], while TRAF3 mutations can be observed in CLL [4,10,11], SMZL [48, 94,95], DLBCL [96] and myeloma [97,98].…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…Richard Rosenquist, 1 Andreas Rosenwald, 2 Ming-Qing Du, 3 Gianluca Gaidano, 4 Patricia Groenen, 5 Andrew Wotherspoon, 6 Paolo Ghia, 7 Philippe Gaulard, 8 Elias Campo, 9 Kostas Stamatopoulos, 10 on behalf of the European Research Initiative on CLL (ERIC) and the European Association for Haematopathology (EAHP) become possible to appreciate the panorama of recurrently affected genes that contribute to disease pathogenesis and/or evolution, at least in major lymphoma subtypes. Mounting evidence suggests that certain gene mutations have diagnostic, prognostic and/or predictive impact.…”

“…3 However, for the great majority of lymphomas, including chronic lymphocytic leukemia (CLL), 4 diffuse large B-cell lymphoma (DLBCL), 5 follicular lymphoma (FL), 6 mantle cell lymphoma (MCL), 7 Burkitt lymphoma (BL), 8 splenic marginal zone lymphoma (SMZL) 9 and most peripheral T-cell lymphoma (PTCL) subtypes, [10][11][12][13] NGS studies have revealed a quite diverse and complex mutation pattern, with a limited number of frequently mutated genes accompanied by a long tail of genes with low-frequency mutations. In addition, while some genes are biased to certain lymphoma entities, e.g.…”

“…From recent NGS studies, the prognostic value of NOTCH1/NOTCH2 mutations was recently highlighted 7,81 in addition to TP53 defects. In DLBCL, the prognostic impact of MYC translocations critically depends on the second hit, with cases harboring TP53 mutation and MYC translocation showing the worst overall survival, followed by those cases carrying MYC and BCL2 translocation.…”