Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

Background: Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues, and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues. Methods: Mosaic mutation detection in 49 normal tissues from 570 individuals (Genotype-Tissue Expression (GTEx) cohort) was performed using a newly developed multi-tissue, multi-individual variant calling approach for RNA-seq data. Our method allows for reliable identification of EMMs and the developmental stage during which they appeared. Results: The analysis of EMMs in 570 individuals revealed that newborns on average harbor 0.5-1 EMMs in the exome affecting multiple organs (1.3230 × 10-8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. Conclusions: In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.This project has received funding from the European Union’s H2020 research and innovation programme under grant agreement no. 635290 (PanCanRisk). We acknowledge support by the Faculty of Medicine of the University of Tübingen, the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017,” SEV-2012-0208, and the CERCA Programme/Generalitat de Catalunya. LZ is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Research Fellowship scheme (846614)

Wavelength-shifting fibers for calorimetric measurements in a long base line neutrino oscillation experiment

The NOE Collaboration has proposed a calorimeter to measure the energy of the final states of v interaction events. The properties of long scintillator bars with wavelength-shifting fiber readout have been studied to develop a calorimeter design option. Various prototypes have been exposed to a cosmic rays stand. The total measured light yield in the middle of a 6 m-long fiber is about 15 photoelectrons. With this photon collection performance, it has been simulated that the calorimeter can achieve 17%/rootE and 50%/rootE resolutions for electrons and pions, respectively. (C) 2001 Elsevier Science B.V. All rights reserved

R&D results from the NOE scintillating fiber calorimeter

The development of the NOE calorimeter, based on scintillating fiber technology, has undergone four years of intense R&D activity. Measurements of light attenuation and time resolution have been carried out on a variety of commercially available scintillating fibers. Both these parameters are important for the optimization of the design of the NOE calorimeter. Experimental results on the fiber attenuation length and light yield make us confident on the possibility to build a 8 x 8 m(2) cross-section calorimeter without noticeable loss of signal. The time resolution is resulted to be of the order of 1 ns, sufficient for up/down discrimination in the final calorimeter setup, by means of the time-of-flight method. Several tests performed to optimize the elementary cell of the calorimeter are also described. (C) 2001 Elsevier Science B.V. All rights reserved

A transition radiation detector interleaved with low-density targets for the NOE experiment

The NOE Collaboration has proposed a transition radiation detector (TRD) interleaved with marble targets to tag the electron decay channel of tau leptons produced by v(tau), eventually originated by upsilon (mu) oscillations in a long base line experiment. A reduced scale TRD detector prototype has been built and exposed to an electron/pion beam at the CERN PS. Discrimination capabilities between electrons and both charged and neutral pions, representing the main source of background for our measurement, have been determined obtaining rejection factors of the order of the tenth of percent for charged pions, and of a few percent for the neutral pion, matching the experiment requirements. The capabilities of this detector to measure the energy released by particles that start showering inside the targets are shown, A momentum resolution sigma (p)/p less than or equal to 40% is found for muons in the range of 1-7 GeV/c. (C) 2001 Elsevier Science B.V. All rights reserved

The NOE scintillating fiber calorimeter prototype test results

An intense R&D program has been carried out by the NOE Collaboration during the last years, to develop a massive fine grain scintillating fiber calorimeter, to be used, in combination with an appropriate target, in a Long Base Line experiment at the CERN to Gran Sasso (CNGS) neutrino beam. The performance of a 4 ton NOE calorimeter prototype exposed to a test beam at CERN PS is shown. Results on the linearity, electromagnetic and hadronic energy resolution are reported and compared with the Monte Carlo predictions. (C) 2001 Elsevier Science B.V. All rights reserved