The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

[1] We document our tomographic method and present a new global model of three-dimensional (3-D) variations in mantle P wave velocity. The model is parameterized by means of rectangular cells in latitude, longitude, and radius, the size of which adapts to sampling density by short-period (1 Hz) data. The largest single data source is ISC/NEIC data reprocessed by Engdahl and coworkers, from which we use routinely picked, short-period P, Pg, Pn, pP, and pwP data (for earthquakes during the period 1964$2007). To improve the resolution in the lowermost and uppermost mantle, we use differential times of core phases (PKP AB À PKP DF , PKP AB À PKP BC , P diff À PKP DF ) and surface-reflected waves (PP-P). The lowfrequency differential times (P diff , PP) are measured by waveform cross correlation. Approximate 3-D finite frequency kernels are used to integrate the long-period data (P diff , PP) and short-period (P, pP, PKP) data. This global data set is augmented with data from regional catalogs and temporary seismic arrays. A crust correction is implemented to mitigate crustal smearing into the upper mantle. We invert the data for 3-D variations in P wave speed and effects of hypocenter mislocation subject to norm and gradient regularization. Spatial resolution is $100 km in the best sampled upper mantle regions. Our model, which is available online and which will be updated periodically, reveals in unprecedented detail the rich variation in style of subduction of lithospheric slabs into the mantle. The images confirm the structural complexity of downwellings in the transition zone discussed in previous papers and show with more clarity the structure of slab fragments stagnant in the transition zone beneath east Asia. They also reveal low wave speed beneath major hot spots, such as Iceland, Afar, and Hawaii, but details of these structures are not well resolved by the data used.Components: 8797 words, 14 figures, 1 table.Keywords: seismic tomography; mantle; traveltimes; P wave speed.

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Tomographic images of the mantle beneath East Asia were obtained from the inversion of traveltime data from global and regional seismograph networks and from temporary arrays on and around the Tibetan plateau. Our results are consistent with previous studies but the unprecedented resolution of mantle heterogeneity provides new insight into the large‐scale tectonic framework of the continental India‐Asia collision in the western part of the study region and subduction of the oceanic lithosphere in the east. In the realm of continental collision, west of ∼100°E, a relatively slow P‐wave speed characterizes the upper mantle beneath much of the Tibetan plateau but the wave speed is high beneath cratonic India, the southern and western part of the Tibetan plateau, Hindu‐Kush, and the Tian Shan. In the subduction realm, east of ∼110°E, the main structures are (i) pronounced low‐wave‐speed anomalies at a depth of between 100 and 400 km beneath Asia's southeastern seaboard and the back‐arc regions of ongoing subduction; (ii) narrow, fast anomalies in the upper mantle beneath major subduction zones; and (iii) widespread fast anomalies at a depth of 500–700 km beneath the Sea of Japan, the northern part of the Philippine Sea plate, and southeastern China. If the latter anomalies represent stagnant slabs, their fragmented nature and large lateral extent suggest that they are produced by different episodes of subduction beneath western Pacific island arcs, along the old SE margin of Asia, or during the Mesozoic collision of cratonic units in Southeast Asia. Attribution to ancient subduction systems implies that slab fragments can reside in the transition zone for (at least) several tens of millions of years. Shallow, slow anomalies beneath the Red River fault region connect to deep anomalies beneath the South China fold belt and South China Sea, suggesting a causal relationship between the evolution of the continental lithosphere of SW China and deeper mantle processes. Between the collision and the subduction realms, tomography reveals high‐wave‐speed continental roots beneath the western part of the North China craton (Ordos block) and the South China, or Yangtze, craton (Sichuan Basin) to a depth of ∼300 km.

BackgroundTGF-β promotes tumor invasion and metastasis through inducing epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in human cancers. However, whether and how circRNAs contribute to TGF-β-induced EMT and metastasis in NSCLC remain vague. Here, we investigated the regulation and function of Circular RNA hsa_circ_0008305 (circPTK2) in TGF-β-induced EMT and tumor metastasis, as well as a link between circPTK2 and transcriptional intermediary factor 1 γ (TIF1γ) in NSCLC.MethodsCircular RNAs were determined by human circRNA Array analysis, real-time quantitative reverse transcriptase PCR and northern blot. Luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were employed to test the interaction between circPTK2 and miR-429/miR-200b-3p. Ectopic overexpression and siRNA-mediated knockdown of circPTK2, TGF-β-induced EMT, Transwell migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPTK2. Transcription and prognosis analyses were done in public databases.ResultsCircPTK2 and TIF1γ were significantly down-regulated in NSCLC cells undergoing EMT induced by TGF-β. CircPTK2 overexpression augmented TIF1γ expression, inhibited TGF-β-induced EMT and NSCLC cell invasion, whereas circPTK2 knockdown had the opposite effects. CircPTK2 functions as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p promote TGF-β-induced EMT and NSCLC cell invasion by targeting TIF1γ. CircPTK2 overexpression inhibited the invasion-promoting phenotype of endogenous miR-429/miR-200b-3p in NSCLC cells in response to TGF-β. CircPTK2 overexpression significantly decreased the expression of Snail, an important downstream transcriptional activator of TGF-β/Smad signaling. In an in vivo experiment of metastasis, circPTK2 overexpression suppressed NSCLC cell metastasis. Moreover, circPTK2 expression was dramatically down-regulated and positively correlated with TIF1γ expression in human NSCLC tissues. Especially, circPTK2 was significantly lower in metastatic NSCLC tissues than non-metastatic counterparts.ConclusionOur findings show that circPTK2 (hsa_circ_0008305) inhibits TGF-β-induced EMT and metastasis by controlling TIF1γ in NSCLC, revealing a novel mechanism by which circRNA regulates TGF-β-induced EMT and tumor metastasis, and suggesting that circPTK2 overexpression could provide a therapeutic strategy for advanced NSCLC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0889-7) contains supplementary material, which is available to authorized users.