Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

A Late Carboniferous-Middle Permian arc/forearc-related basin in Central Asian Orogenic Belt: insights from the petrology and geochemistry of the Shuangjing Schist in Inner Mongolia, China

The Solonker Suture Zone is thought to record the terminal evolution of the Central Asian Orogenic Belt (CAOB) in Inner Mongolia. However, two contrasting interpretations of the timing of suturing of the Solonker Suture Zone exist: (i) Permian to Early Triassic; and (ii) Middle Devonian or Late Devonian to Carboniferous. The Shuangjing Schist is exposed in the Linxi area along the Xar Moron Fault Zone, which marks the southern boundary of the Solonker Suture Zone in the eastern section of the CAOB, and thus provides insight into the timing of suturing of the Solonker Suture Zone. Detailed and systematic analysis of the petrology and geochemistry of the Shuangjing Schist shows that the Shuangjing Schist developed by greenschist facies prograde metamorphism of a volcanisedimentary rock series protolith. The volcanic parts of the Shuangjing Schist are a calc-alkaline series with large volumes of intermediate members and subordinate acidic members. Volcanism occurred in a magmatic arc on the continental margin and was induced by subduction-related magmatism resulting from mantle metasomatism. The sedimentary parts of the Shuangjing Schist reflect a transition from continental shelf to abyssal plain sedimentation. The formation of the Shuangjing Schist is suggested to be related to closure of an arc/forearc-related ocean basin. The timing is constrained by a laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) U-Pb magmatic zircon age of 298±2Ma from a carbonaceous biotite-plagioclase schist that was intruded by granite at 272±2Ma. In the Linxi area, southward subduction of the arc/forearc basin led to uplift, thickening, collapse, and erosion of the overriding continental crust. Collapse induced extension and widespread magmatism along the volcanic arc at the northern margin of the North China Craton. The closure of the arc/forearc-related oceanic basin led to the formation of Late Permian to Middle Triassic collisional granites and the subsequent end of the collision of the Solonker Suture Zone. © 2011 Blackwell Publishing Asia Pty Ltd

Demonstration of dissipative quasihelical edge transport in quantum anomalous hall insulators

Doping a topological insulator (TI) film with transition metal ions can break its time-reversal symmetry and lead to the realization of the quantum anomalous Hall (QAH) effect. Prior studies have shown that the longitudinal resistance of the QAH samples usually does not vanish when the Hall resistance shows a good quantization. This has been interpreted as a result of the presence of possible dissipative conducting channels in magnetic TI samples. By studying the temperature- and magnetic field-dependence of the magnetoresistance of a magnetic TI sandwich heterostructure device, we demonstrate that the predominant dissipation mechanism in thick QAH insulators can switch between non-chiral edge states and residual bulk states in different magnetic field regimes. The interactions between bulk states, chiral edge states, and non-chiral edge states are also investigated. Our study provides a way to distinguish between the dissipation arising from the residual bulk states and non-chiral edge states, which is crucial for achieving true dissipationless transport in QAH insulators and for providing deeper insights into QAH-related phenomena

Unraveling the effects of hydrological connectivity and landscape characteristics on reservoir water quality

Dam construction and reservoir operation altered the landscape and hydrological process of reservoir bays, affecting reservoir water quality. However, many landscape and hydrological connectivity metrics are highly correlated and may introduce redundancies and misleading results when use conventional multivariate regression techniques. Knowledge concerning the pure effects of landscape and hydrological connectivity metrics are crucial for understanding nonpoint pollution processes and guiding water quality protection strategies in reservoirs. Based on water quality monitoring data for six years (2015–2020) from 66 reservoir bays of the Danjiangkou Reservoir in China during both flood discharge periods (FDPs) and water storage periods (WSPs), machine learning approaches (boosted regression trees and random forest) were conducted to decipher the effects of hydrological connectivity and landscape characteristics on water quality. The results showed that landscape composition, landscape configuration, and topography had the combined importance of 46.69%, 31.48%, and 10.14% on the overall water quality changes during the FDPs, respectively. However, landscape configuration was the largest importance factor controlling overall water quality for the WSPs with the combined importance of 38.57%. For the FDPs, the top two importance variables of overall water quality variation were the proportions of shrub and agricultural land in the reservoir bay. For the WSPs, the top two importance variables were flow length and index of connectivity. For specific water quality parameters, the highest importance factor controlling the variation in total nitrogen, total phosphorus, ammonia nitrogen, nitrate and chlorophyll a were landscape configuration, while the landscape composition had the highest importance on the variation in permanganate index, suggesting landscape characteristics affected water quality with specific responses to distinct water quality parameters. These findings emphasize the distinct roles of landscape and hydrological characteristics on water quality and provide important information for the efficient formulation of water quality protection strategies in reservoirs

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research