title: Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Ambrosio
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mundo
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Laginestra
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fuligni
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Sakellarios
authors.initials: S
authors.lastname: Zairis
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gazaneo
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy; School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lazzi
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bellan
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Bruno Jim
authors.initials: BJ
authors.lastname: Rocca
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Amato
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marasco
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Maryam
authors.initials: M
authors.lastname: Etebari
authors.affiliation: Lacor Hospital, Gulu, Uganda.
authors.forename: Martin
authors.initials: M
authors.lastname: Ogwang
authors.affiliation: Lacor Hospital, Gulu, Uganda.
authors.forename: Valeria
authors.initials: V
authors.lastname: Calbi
authors.affiliation: Moi University, Eldoret, Kenya.
authors.forename: Isaac
authors.initials: I
authors.lastname: Ndede
authors.affiliation: Moi University, Eldoret, Kenya.
authors.forename: Kirtika
authors.initials: K
authors.lastname: Patel
authors.affiliation: Moi University, Eldoret, Kenya.
authors.forename: David
authors.initials: D
authors.lastname: Chumba
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy; Unit of Haematopathology, European Institute of Oncology, Milan and Bologna University School of Medicine, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.affiliation: Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy; Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoncini
authors.affiliation: 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.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
mesh_terms: D002051:Burkitt Lymphoma / Q000235:genetics* / Q000821:virology*; D003587:Cytomegalovirus / Q000302:isolation & purification; D004252:DNA Mutational Analysis; D019353:Endemic Diseases; D020031:Epstein-Barr Virus Infections / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D019288:Herpesvirus 8, Human / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D014454:Uganda
chemical_list: D012367:RNA, Viral