Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kB signalling, and we observed mutual exclusivity among tumours with somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

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An increase in the rate of glycolysis is one of the metabolic alterations in most cancer cells. However, the role of alterations in mitochondrial function and mitochondrial DNA (mtDNA) in carcinogenesis still remains unclear. In this study, we analyzed the nucleotide sequence of the D-loop and the copy number of mtDNA in 54 hepatocellular carcinomas (HCCs), 31 gastric, 31 lung, and 25 colorectal cancers as well as their corresponding non-tumorous tissues. The results revealed that 42.6% (23/54) of the HCCs, 51.6% (16/31) of the gastric cancers, 22.6% (7/31) of the lung cancers, and 40.0% (10/25) of the colorectal cancers harbored mutation(s) in the D-loop of mtDNA. The mtDNA mutations in 43.5% (10/23) of the HCCs, 62.5% (10/16) of the gastric cancers, 57.1% (4/7) of the lung cancers, and 90.0% (9/10) of the colorectal cancers were changes in the mononucleotide or dinucleotide repeats, deletions, or multiple insertions. Moreover, we found that there is a significant decrease in mtDNA copy number in 57.4% (31/54) of the HCCs, 54.8% (17/31) of the gastric cancers, 22.6% (7/31) of the lung cancers, and 28.0% (7/25) of the colorectal cancers compared with the corresponding non-tumorous tissues. It is noteworthy that the incidence of somatic mutations in the D-loop of mtDNA in the cancers of later stages was higher than that of the early-stage cancers. Taken together, our findings suggest that instability in the D-loop region of mtDNA, together with the decrease in mtDNA copy number, is involved in the carcinogenesis of human cancers.

BackgroundFriend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver in hematological malignancies and promotes tumor growth in solid tumors. However, little is known about the mechanisms underlying the activation of this proto-oncogene in tumors.ResultsImmunohistochemical staining showed that FLI1 is aberrantly overexpressed in advanced stage and metastatic breast cancers. Using a CRISPR Cas9-guided immunoprecipitation assay, we identify a circular RNA in the FLI1 promoter chromatin complex, consisting of FLI1 exons 4-2-3, referred to as FECR1.Overexpression of FECR1 enhances invasiveness of MDA-MB231 breast cancer cells. Notably, FECR1 utilizes a positive feedback mechanism to activate FLI1 by inducing DNA hypomethylation in CpG islands of the promoter. FECR1 binds to the FLI1 promoter in cis and recruits TET1, a demethylase that is actively involved in DNA demethylation. FECR1 also binds to and downregulates in trans DNMT1, a methyltransferase that is essential for the maintenance of DNA methylation.ConclusionsThese data suggest that FECR1 circular RNA acts as an upstream regulator to control breast cancer tumor growth by coordinating the regulation of DNA methylating and demethylating enzymes. Thus, FLI1 drives tumor metastasis not only through the canonical oncoprotein pathway, but also by using epigenetic mechanisms mediated by its exonic circular RNA.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1594-y) contains supplementary material, which is available to authorized users.

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Chromatin looping is key to gene regulation, yet no broadly applicable methods to selectively modify chromatin loops have been described. We have engineered a method for chromatin loop reorganization using CRISPR-dCas9 (CLOuD9) to selectively and reversibly establish chromatin loops. We demonstrate the power of this technology to selectively modulate gene expression at targeted loci.

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