Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma

Abstract

The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

“…In particular, NOTCH2, known as a key regulator of MZ development, was the most frequently mutated gene (20%) This frequency is consistent with the prevalence of NOTCH2 mutations documented in SMZL 5,6,18,25,26 and significantly higher than that observed in HCV-negative DLBCL (this study), and more in general, in unselected DLBCL cohorts 27,28 (Online Supplementary Table S4). All NOTCH2 mutations observed in HCV-positive DLBCL cause disruption of the protein inhibitory PEST domain and are predicted to activate NOTCH signaling.…”

Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas

“…Subsequent extended studies failed to identify these mutations in thyroid cancer (31) or splenic marginal zone lymphoma (32). In the present study, no TRRAP p.S722 mutations were detected in our ovarian cancer patients with distinct subtypes.…”

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

“…by guest www.bloodjournal.org From methyltransferase-complex subunits, including EED, SUZ12, and EZH2. The latter, the PRC2-complex catalytic subunit, is the target of recurrent somatic mutations in lymphomas including SMZL, 6,34 and its pharmacologic inhibition represents one of the new actively explored therapeutic modalities. [35][36][37] Transcriptional silencing driven by CpG methylation is strictly connected with the activity of the PRC2-complex, which represses expression of differentiation genes through tri-methylation of lysine 27 of histone H3 (H3K27me3).…”

“…Loss of 7q31 and somatic mutations affecting the NOTCH2 gene are the commonest genomic aberrations, with a prevalence of 23% to 26% 2,3 and 7% to 25%, respectively. [4][5][6][7] Deregulation of DNA-promoter methylation has been implicated in B-cell lymphoma pathogenesis and can affect patient outcome. [8][9][10] Aberrant DNA promoter methylation is strictly linked with alterations of the tumor cell epigenome and of the proteins involved in its regulation.…”