Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma
Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma
复制标题
DOI：
10.1182/blood-2018-09-871418
复制
发表时间：
2019-03-21
期刊：
影响因子：
20.3
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Grande, Bruno M.;Gerhard, Daniela S.;Staudt, Louis M.
尽管在资源丰富的地区，伯基特淋巴瘤（BL）通常可以通过强化化疗治愈，但它仍然是老年患者和撒哈拉以南非洲地区的一种致命疾病。在疟疾流行地区，90%以上的病例呈eb病毒阳性，在其他地区，这一比例高达30%。然而，当考虑到肿瘤EBV状态或地理起源时，BL的分子特征尚未得到全面评估。通过对全基因组和转录组数据的综合分析，我们发现EBV阳性肿瘤中异常体细胞超突变在全基因组范围内显著增加，支持EBV与激活诱导的胞苷脱氨酶（AICDA）活性之间的联系。除了发现新的候选BL基因，如SIN3A、USP7和CHD8，我们还证明ebv阳性肿瘤的驱动突变显著减少，特别是在参与细胞凋亡的基因中。我们还发现免疫球蛋白可变区基因在肿瘤中不成比例地用于编码克隆b细胞受体（bcr）。其中包括已知能产生自身反应性抗体的IGHV4-34和IGKV3-20，这一特征在其他b细胞恶性肿瘤中也有描述，但在BL中尚未发现。我们的研究结果表明，肿瘤EBV状态决定了特定的BL表型，与地理起源无关，具有特定的分子特性和独特的致病机制。本研究发现的新突变模式意味着一些BL患者应合理使用dna损伤化疗，而其他BL患者应使用靶向药物，如CDK4/6抑制剂帕博西尼，而BCR信号在BL中的重要性增强了这些患者使用PI3K、Syk和Src家族激酶抑制剂的潜在益处。
Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.