We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Epstein–Barr virus (EBV), originally discovered through its association with Burkitt lymphoma, is now aetiologically linked to a remarkably wide range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. Some occur as rare accidents of virus persistence in the B lymphoid system, while others arise as a result of viral entry into unnatural target cells. The early finding that EBV is a potent B-cell growth transforming agent hinted at a simple oncogenic mechanism by which this virus could promote lymphomagenesis. In reality, the pathogenesis of EBV-associated lymphomas involves a complex interplay between different patterns of viral gene expression and cellular genetic changes. Here we review recent developments in our understanding of EBV-associated lymphomagenesis in both the immunocompetent and immunocompromised host. This article is part of the themed issue ‘Human oncogenic viruses’.

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Epstein–Barr virus-associated lymphomas

There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.

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Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias

Epstein-Barr virus (EBV), a gamma-1 herpesvirus, is carried as a life-long asymptomatic infection by the great majority of individuals in all human populations. Yet this seemingly innocent virus is aetiologically linked to two pre-malignant lymphoproliferative diseases (LPDs) and up to nine distinct human tumors; collectively these have a huge global impact, being responsible for some 200,000 new cases of cancer arising worldwide each year. EBV replicates in oral epithelium but persists as a latent infection within the B cell system and several of its diseases are indeed of B cell origin; these include B-LPD of the immunocompromised, Hodgkin Lymphoma (HL), Burkitt Lymphoma (BL), Diffuse Large B cell Lymphoma (DLBCL) and two rarer tumors associated with profound immune impairment, plasmablastic lymphoma (PBL) and primary effusion lymphoma (PEL). Surprisingly, the virus is also linked to tumors arising in other cellular niches which, rather than being essential reservoirs of virus persistence in vivo, appear to represent rare cul-de-sacs of latent infection. These non-B cell tumors include LPDs and malignant lymphomas of T or NK cells, nasopharyngeal carcinoma (NPC) and gastric carcinoma of epithelial origin, and leiomyosarcoma, a rare smooth muscle cell tumor of the immunocompromised. Here we describe the main characteristics of these tumors, their distinct epidemiologies, histological features and degrees of EBV association, then consider how their different patterns of EBV latency may reflect the alternative latency programmes through which the virus first colonizes and then persists in immunocompetent host. For each tumor, we discuss current understanding of EBV's role in the oncogenic process, the identity (where known) of host genetic and environmental factors predisposing tumor development, and the recent evidence from cancer genomics identifying somatic changes that either complement or in some cases replace the contribution of the virus. Thereafter we look for possible connections between the pathogenesis of these apparently different malignancies and point to new research areas where insights may be gained.

The Global Landscape of EBV-Associated Tumors.

The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.

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Sexual dimorphism in cancer.

Zhu Chen, Sai-Juan Chen, Wei-Li Zhao and colleagues identify recurrent loss-of-function mutations in the RNA helicase gene DDX3X in 20% of subjects with natural killer/T-cell lymphoma (NKTCL) in their study. The results suggest that DDX3X acts as a tumor suppressor and that its inactivation leads to poor clinical outcome.

Zi-Min Sun

Papers

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma