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...

In the present series, the primary site of disease was associated with particular clinicopathologic features and outcome, though the latter largely depended on other factors.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm initially driven by CCND1 rearrangement with two molecular subtypes, conventional (cMCL) and leukemic non-nodal (nnMCL), that differ in their clinicobiological behavior. To identify the genetic/epigenetic alterations determining this diversity, we used whole-genome (n=61) and exome (n=21) sequencing (74% cMCL, 26% nnMCL) combined with transcriptome and DNA methylation profiles in the context of five MCL reference epigenomes. We identified that open and active chromatin at the major translocation cluster locus might facilitate the t(11;14)(q13;32), which modifies the 3-dimensional structure of the involved regions. This translocation is mainly acquired in precursor B cells mediated by RAG in both MCL subtypes, while in 8% of cases occurs in mature B cells mediated by AID. We identified novel recurrent MCL drivers, including CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1. Complex structural alterations emerge as a relevant early oncogenic mechanism in MCL targeting key driver genes. Breakage-fusion bridge cycles and translocations activated oncogenes (BMI1, MIR17HG, TERT, MYC, and MYCN), generating gene amplifications and remodeling regulatory regions. cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL, whereas TP53 and TERT alterations were slightly enriched in nnMCL. Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. An increasing genomic complexity together with the presence of breakage-fusion bridge cycles and high DNA methylation changes related to the proliferative cell history discriminate patients with different clinical evolution.

The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 lowrisk patients with ET treated with antiplatelet drugs as monotherapy (n ‫؍‬ 198) or followed with careful observation (n ‫؍‬ 102).

IntroductionChronic lymphocytic leukemia (CLL) is a frequent malignancy composed of CD5 ϩ B lymphocytes, is predominant in older people, and has a variable clinical course. The median survival of patients with CLL is approximately 10 years, but the individual prognosis is extremely variable. Whereas in some patients the disease runs an indolent clinical course and their life span is not shortened, in others the disease has an aggressive behavior with a survival of less than 2 to 3 years. 1,2 Management of patients with CLL is one of the most challenging situations in hemato-oncology. For decades treatment of this disease revolved around the use of alkylating agents with little or no effect on the natural history of the disease. The introduction in the late 1980s of purine analogs signified an important breakthrough in the management of CLL. More recently, chemoimmunotherapy has emerged as the new paradigm for therapy of CLL. [3][4][5] Whether new treatments, along with better general medical care, improve survival of patients with CLL is not completely clear. The analysis of historical series suggests a better survival for patients treated with modern therapies, but these analyses are biased by different median follow-up times and do not take into consideration the natural increase in the life expectancy of the general population. [4][5][6][7] In addition, recent randomized studies have shown a longer progression-free, but not a longer overall, survival in patients receiving newer treatments. 8,9 Yet the advantage of a given therapy over another in randomized studies, taking overall survival as end point, is difficult to establish because of the effect on patients' outcome of subsequent, rescue treatments. Finally, data from the Surveillance, Epidemiology, and End Results Program of the US National Cancer Institute (www.seer.cancer.gov) indicate that there is a survival improvement in those patients most recently diagnosed, with the only exception of the elderly. 10 However, registry studies have some limitations, such as underreporting and late reporting, which makes it difficult to ascertain recent progress in survival. 11 The analysis of large series of patients from single institutions offers an important opportunity to investigate recent changes in the prognosis and survival patterns of CLL. The aim of this study was to investigate presentation features and survival over the time in a large series of patients with CLL seen at the Hospital Clínic of Barcelona. Methods PatientsIn total, 929 patients diagnosed with CLL between January 1980 and December 2008 and followed at the Hospital Clínic of Barcelona were evaluated. All patients were diagnosed in agreement with the National Cancer Institute-Working Group Criteria. 12 In addition by excluding patients diagnosed before 1980 we assured that diagnosis was confirmed by flow cytometry in all patients. Demographic characteristics and clinical and laboratory features at presentation, as well as treatment methods and follow-up data, were obtained from a database t...