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

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.

脾边缘区淋巴瘤（splenic marginal zone lymphoma, SMZL）的发病机制目前仍未完全阐明。近期的高通量测序研究已在关键通路中发现复发性突变，其中超过25%的患者存在NOTCH2基因突变。此类研究均基于小型异质性发现队列，因此仅捕捉到了SMZL基因组中存在的部分病变。为进一步鉴定相关生化通路中的新型致病突变，本研究对由7例携带7号染色体长臂（7q）异常且存在IGHV1-2*04基因使用特征的SMZL患者组成的生物学与临床均质性队列，开展了全外显子组测序（whole exome sequencing, WES）与拷贝数（copy number, CN）分析。本研究共鉴定出173个体细胞非同义变异，涉及160个不同的基因。除对既往报道的数个基因（NOTCH2、TNFAIP3、MAP3K14、MLL2及SPEN）的突变存在性进行独立验证外，本研究还明确了SMZL中另外8个复发性突变基因：CREBBP、CBFA2T3、AMOTL1、FAT4、FBXO11、PLA2G4D、TRRAP及USH2A。通过整合全外显子组测序与拷贝数分析数据，本研究鉴定出3个受7q缺失靶向的突变候选致病基因：CUL1、EZH2及FLNC，其中FLNC位于已被充分表征的7q最小缺失区域内。综上，本研究拓展了该疾病中已报道的复发性突变癌基因目录，从而加深了我们对SMZL发病机制的理解。最终，本研究将助力建立分层诊疗方案，其中包括靶向治疗的应用可能。