Abate Francesco, Ambrosio Maria Raffaella, Mundo Lucia, Laginestra Maria Antonella, Fuligni Fabio, Rossi Maura, Zairis Sakellarios, Gazaneo Sara, De Falco Giulia, Lazzi Stefano, Bellan Cristiana, Rocca Bruno Jim, Amato Teresa, Marasco Elena, Etebari Maryam, Ogwang Martin, Calbi Valeria, Ndede Isaac, Patel Kirtika, Chumba David, Piccaluga Pier Paolo, Pileri Stefano, Leoncini Lorenzo, Rabadan Raul
Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America; Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
PLoS Pathog. 2015 Oct 15;11(10):e1005158. doi: 10.1371/journal.ppat.1005158. eCollection 2015 Oct.
Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.
地方性伯基特淋巴瘤（eBL）主要见于赤道地区的儿童，是病毒相关人类恶性肿瘤的首个历史实例。尽管爱泼斯坦-巴尔病毒（EBV）感染和MYC易位是该疾病的标志，但尚不清楚其他因素是否可能促成其发展。我们对来自乌干达的20例eBL病例进行了RNA测序，结果表明eBL的突变和病毒格局比先前报道的更为复杂。首先，我们在8例（40%）病例中发现了其他疱疹病毒科成员的存在，特别是人类疱疹病毒5型和人类疱疹病毒8型，并通过免疫组织化学在相邻的非肿瘤组织中证实了它们的存在。其次，我们在EBV中确定了一种独特的潜伏程序，涉及与TCF3活性相关的裂解基因。第三，通过将eBL的突变格局与散发性伯基特淋巴瘤（sBL）的已发表数据进行比较，我们在eBL样本中检测到MYC、ID3、TCF3和TP53的突变频率较低，而ARID1A的突变频率较高。在20%的肿瘤中发现了两个先前与eBL无关的基因的复发性突变：RHOA和细胞周期蛋白F（CCNF）。我们还观察到，与sBL标本相比，多病毒样本在常见改变基因中的体细胞突变数量较少，这表明分别在sBL和eBL中存在转化的双重机制，即突变驱动和病毒驱动。
