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.

ersistent HPV infection, in episomal or integrated form, is necessary but not sufficient for the development of cervical cancer 1. HPV-16 and HPV-18 are detected in at least 70% of affected individuals 2. HPV-16 (clade A9) is common in both squamous cell carcinomas and adenocarcinomas, while HPV-18 (clade A7) is associated with adenocarcinomas 2 and inferior survival 3-5. Cervical cancer prevention strategies include vaccination and screening for HPV and treatment of high-grade precancer. Although effective 6 , vaccine use remains low in low-and middle-income countries 7 where HIV is prevalent. Resource constraints similarly complicate screening, surgery 8 and radiotherapy 9 , such that a 50% increase in cervical cancer mortality by 2040 is predicted 10. Genomic cervical cancer studies, primarily conducted in non-African individuals 11,12 , identified APOBEC mutational signatures, copy number amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2), somatic alterations affecting the PI(3)K-MAPK and TGFβR2 pathways 11,12 and mutations in chromatin modifier genes 11-13. Studies in HPV-infected individuals with head and neck squamous cell carcinomas linked HPV integration to changes in histone modification 14 and DNA methylation 15 , suggesting the potential for similar findings in cervical cancer. As part of the National Cancer Institute's (NCI's) HIV+ Tumor Molecular Characterization Project (HTMCP), we characterized the genomic, transcriptomic and epigenomic landscapes of cervical cancers from Ugandan patients. We identified previously uncharacterized differences in the epigenomes and transcriptomes of cervical tumors from individuals infected by different HPV clades and note that these clades appear relevant to prognosis. Results Patient samples and clinical data. Our cohort of 212 patients with cervical cancer received treatment at the Uganda Cancer Institute in Kampala. Of these, 118 made up our discovery cohort and 89 made up our extension cohort (Supplementary Tables 1 and 2, and Methods). HIV + patients (72/118, 61%) were 10 years younger, on average, than HIV-negative (HIV-) patients (mean, 42.9 versus 52.4 years).

Recently, mitochondria have been suggested to act in tumor suppression. However, the underlying mechanisms by which mitochondria suppress tumorigenesis are far from being clear. In this study, we have investigated the link between mitochondrial dysfunction and the tumor suppressor protein p53 using a set of respiration-deficient (Res ؊ ) mammalian cell mutants with impaired assembly of the oxidative phosphorylation machinery. Our data suggest that normal mitochondrial function is required for ␥-irradiation (␥IR)-induced cell death, which is mainly a p53-dependent process. The Res ؊ cells are protected against ␥IR-induced cell death due to impaired p53 expression/ function. We find that the loss of complex I biogenesis in the absence of the MWFE subunit reduces the steady-state level of the p53 protein, although there is no effect on the p53 protein level in the absence of the ESSS subunit that is also essential for complex I assembly. The p53 protein level was also reduced to undetectable levels in Res ؊ cells with severely impaired mitochondrial protein synthesis. This suggests that p53 protein expression is differentially regulated depending upon the type of electron transport chain/respiratory chain deficiency. Moreover, irrespective of the differences in the p53 protein expression profile, ␥IR-induced p53 activity is compromised in all Res ؊ cells. Using two different conditional systems for complex I assembly, we also show that the effect of mitochondrial dysfunction on p53 expression/function is a reversible phenomenon. We believe that these findings will have major implications in the understanding of cancer development and therapy.Mitochondrial dysfunction is associated with aging, degenerative diseases, and cancer (1-3). One of the key functions of mitochondria is to make ATP by the process of oxidative phosphorylation (OxPhos), 2 which is carried out by four electron transport chain (ETC)/respiratory chain (RC) complexes (I-IV) and the ATP synthase (complex V). The OxPhos machinery consists of over 100 nuclear and mitochondrial DNA-encoded proteins (4). Thirteen proteins encoded by mitochondrial (mt) DNA are core proteins of complexes I and III-V that are synthesized inside mitochondria. Complex II is an exception as all of its subunits are encoded by nuclear genes. Mutations in both mtDNA and nuclear genes encoding OxPhos complexes are associated with almost all types of cancers (1, 3). Somatic mutations in complex I subunit-encoding genes are frequently associated with oncocytomas (5, 6). A recent study with head and neck cancers suggests that there are no mutational hot spots in the mtDNA (7). However, other studies suggest that mtDNA polymorphisms may predispose certain populations to cancer (8 -12). The association of germ line mutations in complex II subunits with hereditary paragangliomas and pheochromocytomas constitute the strongest evidence for implicating mitochondrial metabolism in tumorigenesis (13,14). Furthermore, the association of reduced expression of several subunits of OxPhos comple...