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.

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.

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. 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. 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. 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.

Human herpesvirus 8 (HHV-8) infection is common in Africa. We examined the distribution of HHV-8 within families in rural Tanzania to determine route