Sam M. Mbulaiteye

Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics

Burkitt’s lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein–Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.

Immune deficiency and risk for malignancy among persons with AIDS.

Background People with AIDS have an elevated risk for cancer. We studied the relationship between cancer risk and AIDS-related immunosuppression as measured by CD4 count at AIDS onset. Methods We linked records from AIDS and cancer registries in 11 US regions (1990–1996). We studied 82,217 (86.6%) adults who had a CD4 count measured at AIDS onset and survived into the follow-up period. We calculated standardized incidence ratios (SIRs) for AIDS-defining (Kaposi sarcoma [KS], non-Hodgkin lymphoma [NHL] and cervical cancer) as well as non-AIDS-defining cancers in the 2 years after AIDS onset. For each cancer, the change in SIRs across CD4 counts (0–49 cells/mm3, 50–99 cells/mm3, 100–199 cells/mm3, and ≥200 cells/mm3) was modeled using Poisson regression. Results The SIRs for KS, NHL, and cervical cancer were 258, 78, and 8.8, respectively. For each fall of 100 CD4 cells/mm3, RRs were 1.36 (95% CI: 1.29–1.43) for KS and 1.48 (95% CI: 1.37–1.59) for NHL. Among NHL subtypes, the association with lower CD4 counts was strongest for immunoblastic lymphoma (RR =1.64, 95% CI: 1.37–1.96, per decline of 100 CD4 cells/mm3) and central nervous system lymphoma (RR = 2.29, 95% CI: 1.95–2.69). The SIR for cervical cancer did not vary with CD4 count (p = .74). For non-AIDS-defining cancers (overall SIR = 2.1), neither the combined risk nor the risk of specific types was associated with declining CD4 counts. Conclusions KS and NHL risk increased with level of immunosuppression at AIDS onset. Risks for other cancers, including cervical cancer, were unrelated to CD4 counts. Elevated risks for non-AIDS cancers may be a result of lifestyle factors.

Spectrum of cancers among HIV-infected persons in Africa : The Uganda AIDS-Cancer Registry Match Study

Although more than 25 million people in sub‐Saharan Africa have human immunodeficiency virus (HIV) infection, little is known regarding their cancer risk. We investigated cancer risk among persons with HIV/AIDS in Uganda using record‐linkage. We linked records of 12,607 HIV‐infected persons attending The AIDS Support Organization (TASO) in Kyadondo County from October 1988 through December 2002 to the Kampala Cancer Registry. We calculated standardized incidence ratios (SIRs) to identify increased cancer risks in the early (4–27 months after TASO registration), late (28–60 months), or combined (4–60 months) incidence periods. We identified 378 cancers (181 prevalent, 197 incident) among TASO participants. Of incident cancers, 137 (70%) were AIDS‐defining cancers. Risk was increased in the early‐incident period, compared to the general population, for the AIDS‐defining cancers: Kaposi sarcoma (SIR 6.4, 95%CI 4.8–8.4), non‐Hodgkin lymphoma (6.7, 1.8–17), and cervical carcinoma (2.4, 1.1–4.4). These three cancers were also increased in the combined periods. Risks of five non‐AIDS‐defining cancers were increased in the combined periods: Hodgkin lymphoma (5.7, 1.2–17) and cancers of the conjunctiva (SIR 4.0; 1.5–8.7), kidney (16, 1.8–58), thyroid (5.7, 1.1–16), and uterus (5.5, 1.5–14). Cancers of the breast, nasopharynx, and lung were increased either in the early or late incident periods only. Among 407 children, seven cancers were observed, of which five were Kaposi sarcoma. The application of a record‐linkage design in Africa broadens the repertoire of epidemiological tools for studying HIV‐infected populations. We confirm the increased risks of AIDS‐defining cancers and report increased risks of a few non‐AIDS‐defining cancers.

Human herpesvirus 8 infection within families in rural Tanzania

Human herpesvirus 8 (HHV-8) infection is common in Africa. We examined the distribution of HHV-8 within families in rural Tanzania to determine routes of spread. HHV-8 infection was assessed by measuring antibody reactivity with a K8.1 (lytic-phase antigen) immunoassay. The prevalence increased from 3.7% (1/27) among infants to 58.1% (36/62) among children aged 3-4 years and 89.0% (65/73) among adults aged > or =45 years. Women with HHV-8-seropositive husbands had a 7-fold risk for infection (odds ratio [OR], 6.9; 95% confidence interval [CI], 1.9-25.3). HHV-8 seropositivity in children was associated with having at least 1 seropositive first-degree relative (OR, 14.7; 95% CI, 5.9-43.1), a seropositive mother (OR, 7.4; 95% CI, 3.2-16.8), a seropositive father (OR, 4.8; 95% CI, 2.3-10.1), or a seropositive next-older sibling (OR, 4.2; 95% CI, 1.9-9.4). Our data are consistent with the occurrence of HHV-8 transmission within families, from mothers and other relatives to children via nonsexual routes and between spouses via sexual routes.

A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda.

Uganda offers a unique setting in which to study the effect of human immunodeficiency virus‐1 (HIV‐1) on cancer. HIV‐1 is prevalent there, and cancers which are known to be HIV‐associated, such as Kaposis sarcoma and Burkitts lymphoma, are endemic. Adults residing in Kampala, Uganda, presenting with cancer in city hospitals were interviewed and had an HIV test. Of the 302 adults recruited, 190 had cancers with a potentially infectious aetiology (cases). The remaining 112 adults with tumours not known to have an infectious aetiology formed the control group. In addition, 318 children who were also Kampala residents were recruited and tested for HIV: 128 with cancer (cases) and 190 with non‐malignant conditions (controls). HIV seroprevalence was 24% in adult controls and 6% in childhood controls. The odds of HIV seropositivity among cases with specific cancers (other than Kaposis sarcoma in adults) were compared with that among controls, using odds ratios (ORs), estimated with unconditional logistic regression. All ORs were adjusted for age (<5, 5–14, 15–19, 30–44, 45+) and sex and, in adults, also for the number of lifetime sexual partners (1 or 2, 3–9, 10+). In adults, HIV infection was associated with a significantly (p < 0.05) increased risk of non‐Hodgkins lymphoma [OR = 6.2, 95% confidence interval (CI) 1.9–19.9, based on 21 cases] and conjunctival squamous‐cell carcinoma (OR = 10.9, 95% CI 3.1–37.7, based on 22 cases) but not with cancer at other common sites, including liver and uterine cervix. In children, HIV infection was associated with a significantly increased risk of Kaposis sarcoma (OR = 94.9, 95% CI 28.5–315.3, based on 36 cases) and Burkitts lymphoma (OR = 7.5, 95% CI 2.8–20.1, based on 33 cases) but not with other cancers. The pattern of HIV‐associated cancers in Uganda is broadly similar to that described elsewhere, but the relative frequency of specific cancers, such as conjunctival carcinoma, in HIV‐infected people differs.

The extent of genetic diversity of Epstein-Barr virus and its geographic and disease patterns: a need for reappraisal.

Epstein-Barr virus (EBV) is a ubiquitous, gamma-1 lymphotrophic virus etiologically linked to nasopharyngeal carcinoma (NPC), endemic to Southern China, and Burkitt lymphoma (BL), endemic to equatorial Africa, both of which are rare elsewhere in the world. Why EBV is associated with different malignancies in different geographic regions remains puzzling and may be related to EBV genotypic variability through specific disease and geographic associations. We review the literature on sequence variation in EBV genes, focusing on LMP-1, EBNA-1, and BZLF-1 and their distribution by geography and disease. Given the limitations of current studies, definitive conclusions regarding the link between EBV genotypes, disease and geography are not possible. We suggest that the true extent of EBV diversity is likely to be greater than is currently recognized. Additional studies conducted in carefully selected populations, that are sufficiently powered to provide robust estimates, and that utilize testing approaches that permit full characterization of viral diversity are needed to further our understanding of patterns of EBV genetic variation and their association with malignancies in different regions.

Epidemiology of AIDS-related malignancies: An international perspective

Patients with HIV infection are at increased risk for developing Kaposis sarcoma, non-Hodgkins lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population--lung, breast, colon/rectum, stomach, liver, and prostate--are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkins lymphoma, cervical carcinoma in situ (CIS), other anogenital neoplasms (invasive cancer and CIS), leiomyosarcoma, and conjunctival squamous cell carcinoma. There is inconclusive evidence, however, with regard to HIV infection being associated with invasive cervical cancer, testicular seminoma, or hepatocellular carcinoma. Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk.

Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

BACKGROUND Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. METHODS We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). RESULTS Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. CONCLUSIONS Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

The epidemiology of conjunctival squamous cell carcinoma in Uganda

As part of a larger investigation of cancer in Uganda, we conducted a case–control study of conjunctival squamous cell carcinoma in adults presenting at hospitals in Kampala. Participants were interviewed about social and lifestyle factors and had blood tested for antibodies to HIV, KSHV and HPV-16, -18 and -45. The odds of each factor among 60 people with conjunctival cancer was compared to that among 1214 controls with other cancer sites or types, using odds ratios, estimated with unconditional logistic regression. Conjunctival cancer was associated with HIV infection (OR 10.1, 95% confidence intervals [CI] 5.2–19.4; P<0.001), and was less common in those with a higher personal income (OR 0.4, 95% CI 0.3–1.2; P<0.001). The risk of conjunctival cancer increased with increasing time spent in cultivation and therefore in direct sunlight (χ2 trend=3.9, P=0.05), but decreased with decreasing age at leaving home (χ2 trend=3.9, P=0.05), perhaps reflecting less exposure to sunlight consequent to working in towns, although both results were of borderline statistical significance. To reduce confounding, sexual and reproductive variables were examined among HIV seropositive individuals only. Cases were more likely than controls to report that they had given or received gifts for sex (OR 3.5, 95% CI 1.2–10.4; P=0.03), but this may have been a chance finding as no other sexual or reproductive variable was associated with conjunctival cancer, including the number of self-reported lifetime sexual partners (P=0.4). The seroprevalence of antibodies against HPV-18 and -45 was too low to make reliable conclusions. The presence of anti-HPV-16 antibodies was not significantly associated with squamous cell carcinoma of the conjunctiva (OR 1.5, 95% CI 0.5–4.3; P=0.5) and nor were anti-KSHV antibodies (OR 0.9, 95% CI 0.4–2.1; P=0.8). The 10-fold increased risk of conjunctival cancer in HIV infected individuals is similar to results from other studies. The role of other oncogenic viral infections is unclear.

Helicobacter Pylori associated global gastric cancer burden.

Helicobacter pylori infection is ubiquitous, infecting close to one-half of the worlds population, but its prevalence is declining in developed countries. Chronic H. pylori infection is etiologically linked to gastric adenocarcinoma, especially non-cardia type (63% of all stomach cancer or ~5.5% of the global cancer burden: ~25% of cancers associated with infectious etiology), and to gastric mucosal associated lymphoid tissue (MALT) lymphoma, which accounts for up to 8% of all non-Hodgkin lymphoma. Epidemiological, clinical, and animal studies have established a central role for H. pylori in gastric carcinogenesis and provided insights into the mechanisms and biologic relationships between bacterial infection, host genetics, nutrition, and environmental factors. These discoveries invite strategies to prevent infection to be the logical primary goals in a multi-pronged effort to curtail suffering and death from H. pylori infection-associated cancers.