Emily Rogena

The different epidemiologic subtypes of Burkitt lymphoma share a homogenous micro RNA profile distinct from diffuse large B-cell lymphoma

Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants—sBL, endemic BL (eBL) and human immunodeficiency virus-associated BL (HIV-BL)—represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of Epstein–Barr virus (EBV) infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs containing MYC regulated and nuclear factor-kB pathway-associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only six differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL.

Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes

To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL), we performed clinical-grade next-generation sequencing of 182 cancer-related genes on 29 formalin-fixed, paraffin embedded primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (P < .0001). Alterations in tumor-related genes not previously described in BL were identified. Truncating mutations in ARID1A, a member of the SWI/SNF nucleosome remodeling complex, were seen in 17% of cases. MCL1 pathway alterations were found in 22% of cases and confirmed in an expanded panel. Other clinically relevant genomic alterations were found in 20% of cases. Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that comprehensive genomic profiling may identify additional treatment options in refractory disease.

Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research?

Approximately 30 000 cases of non‐Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub‐Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub‐Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub‐Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B‐cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T‐cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub‐Saharan Africa for fostering high‐quality translational research.

Burkitt lymphoma versus diffuse large B-cell lymphoma: a practical approach

Burkitt Lymphoma (BL) is listed in the World Health Organization (WHO) classification of lymphoid tumours as an ‘aggressive B‐cell non‐Hodgkins lymphoma’, characterized by a high degree of proliferation of the malignant cells and deregulation of the c‐MYC gene. The main diagnostic challenge in BL is to distinguish it from diffuse large B‐cell lymphoma (DLBCL). While in children BL and DLBCL types probably do not differ clinically, and the differential diagnosis between BL and DLBCL may theoretically appear clear‐cut, in adults daily practice shows the existence of cases that have morphological features, immunophenotypic and cytogenetics intermediate between DLBCL and BL, and cannot be classified with certainty in these categories. Distinguishing between BL and DLBCL is critical, as the two diseases require different management. This review summarizes the current practical approach, including the use of a large panel of antibodies, and cytogenetic and molecular diagnostic techniques, to distinguish between BL, DLBCL and the provisional category of ‘B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma’, now listed in the updated WHO classification. Copyright

Diagnosis of Burkitt lymphoma using an algorithmic approach – applicable in both resource‐poor and resource‐rich countries

Distinguishing Burkitt lymphoma (BL) from B cell lymphoma, unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and BL (DLBCL/BL), and DLBCL is challenging. We propose an immunohistochemistry and fluorescent in situ hybridization (FISH) based scoring system that is employed in three phases – Phase 1 (morphology with CD10 and BCL2 immunostains), Phase 2 (CD38, CD44 and Ki‐67 immunostains) and Phase 3 (FISH on paraffin sections for MYC, BCL2, BCL6 and immunoglobulin family genes). The system was evaluated on 252 aggressive B‐cell lymphomas from Europe and from sub‐Saharan Africa. Using the algorithm, we determined a specific diagnosis of BL or not‐BL in 82%, 92% and 95% cases at Phases 1, 2 and 3, respectively. In 3·4% cases, the algorithm was not completely applicable due to technical reasons. Overall, this approach led to a specific diagnosis of BL in 122 cases and to a specific diagnosis of either DLBCL or DLBCL/BL in 94% of cases that were not diagnosed as BL. We also evaluated the scoring system on 27 cases of BL confirmed on gene expression/microRNA expression profiling. Phase 1 of our scoring system led to a diagnosis of BL in 100% of these cases.

Delivering post-rape care services: Kenya's experience in developing integrated services

PROBLEM Comprehensive service delivery models for providing post-rape care are largely from resource-rich countries and do not translate easily to resource-limited settings such as Kenya, despite an identified need and high rates of sexual violence and HIV. APPROACH Starting in 2002, we undertook to work through existing governmental structures to establish and sustain health sector services for survivors of sexual violence. LOCAL SETTING In 2003 there was a lack of policy, coordination and service delivery mechanisms for post-rape care services in Kenya. Post-exposure prophylaxis against HIV infection was not offered. RELEVANT CHANGES A standard of care and a simple post-rape care systems algorithm were designed. A counselling protocol was developed. Targeted training that was knowledge-, skills- and values-based was provided to clinicians, laboratory personnel and trauma counsellors. The standard of care included clinical evaluation and documentation, clinical management, counselling and referral mechanisms. Between early 2004 and the end of 2007, a total of 784 survivors were seen in the three centres at an average cost of US

Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas.

27, with numbers increasing each year. Almost half (43%) of these were children less than 15 years of age. LESSONS LEARNED This paper describes how multisectoral teams at district level in Kenya agreed that they would provide post-exposure prophylaxis, physical examination, sexually transmitted infection and pregnancy prevention services. These services were provided at casualty departments as well as through voluntary HIV counselling and testing sites. The paper outlines which considerations they took into account, who accessed the services and how the lessons learned were translated into national policy and the scale-up of post-rape care services through the key involvement of the Division of Reproductive Health.

HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas

Burkitt lymphoma (BL) is an aggressive neoplasm characterized by consistent morphology and phenotype, typical clinical behavior and distinctive molecular profile. The latter is mostly driven by the MYC over-expression associated with the characteristic translocation (8;14) (q24; q32) or with variant lesions. Additional genetic events can contribute to Burkitt Lymphoma pathobiology and retain clinical significance. A pathogenetic role for Epstein-Barr virus infection in Burkitt lymphomagenesis has been suggested; however, the exact function of the virus is largely unknown. In this study, we investigated the molecular profiles (genes and microRNAs) of Epstein-Barr virus-positive and -negative BL, to identify specific patterns relying on the differential expression and role of Epstein-Barr virus-encoded microRNAs. First, we found significant differences in the expression of viral microRNAs and in selected target genes. Among others, we identified LIN28B, CGNL1, GCET2, MRAS, PLCD4, SEL1L, SXX1, and the tyrosine kinases encoding STK10/STK33, all provided with potential pathogenetic significance. GCET2, also validated by immunohistochemistry, appeared to be a useful marker for distinguishing EBV-positive and EBV-negative cases. Further, we provided solid evidences that the EBV-encoded microRNAs (e.g. BART6) significantly mold the transcriptional landscape of Burkitt Lymphoma clones. In conclusion, our data indicated significant differences in the transcriptional profiles of EBV-positive and EBV-negative BL and highlight the role of virus encoded miRNA.

A review of the trends of lymphomas in the equatorial belt of Africa

BackgroundA close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents.MethodsHIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas.In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects.ResultsOur results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down-regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells.ConclusionsOur findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs.These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression.

Correlation of EGFR, pEGFR and p16INK4 expressions and high risk HPV infection in HIV/AIDS-related squamous cell carcinoma of conjunctiva

Lymphomas represent one of the most frequent cancer types in Africa. In particular, approximately 30 000 non‐Hodgkin lymphomas occur in the equatorial belt of Africa each year and these tumours are in among the top‐ten cancers in this geographical region. Several pathogens and environmental factors have been detected in association with these tumours, suggesting that they may contribute to lymphomagenesis. Unfortunately, there are still striking differences between developed and African countries in terms of early detection, diagnosis and treatment of lymphomas. Of note, the disease burden appears to be increasing in Africa. In addition, a much lower cure rate in the low‐income countries suggests that the difference in mortality will even become more pronounced in future. Therefore, improving diagnosis is crucial as without it, neither meaningful research projects nor effective patient management can be instituted. In this review, we will summarize the state‐of‐the‐art of lymphoma epidemiology, pathobiology and therapy, and will highlight the still existing gaps between developed and African countries. Copyright