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

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

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

Obtención de un conjunto de datos derivados de la HCE para investigación en VIH: prueba de concepto

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613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review

Background Rupture of the spleen in the absence of trauma or previously diagnosed disease is largely ignored in the emergency literature and is often not documented as such in journals from other fields. We have conducted a systematic review of the literature to highlight the surprisingly frequent occurrence of this phenomenon and to document the diversity of diseases that can present in this fashion. Methods Systematic review of English and French language publications catalogued in Pubmed, Embase and CINAHL between 1950 and 2011. Results We found 613 cases of splenic rupture meeting the criteria above, 327 of which occurred as the presenting complaint of an underlying disease and 112 of which occurred following a medical procedure. Rupture appeared to occur spontaneously in histologically normal (but not necessarily normal size) spleens in 35 cases and after minor trauma in 23 cases. Medications were implicated in 47 cases, a splenic or adjacent anatomical abnormality in 31 cases and pregnancy or its complications in 38 cases. The most common associated diseases were infectious (n = 143), haematologic (n = 84) and non-haematologic neoplasms (n = 48). Amyloidosis (n = 24), internal trauma such as cough or vomiting (n = 17) and rheumatologic diseases (n = 10) are less frequently reported. Colonoscopy (n = 87) was the procedure reported most frequently as a cause of rupture. The anatomic abnormalities associated with rupture include splenic cysts (n = 6), infarction (n = 6) and hamartomata (n = 5). Medications associated with rupture include anticoagulants (n = 21), thrombolytics (n = 13) and recombinant G-CSF (n = 10). Other causes or associations reported very infrequently include other endoscopy, pulmonary, cardiac or abdominal surgery, hysterectomy, peliosis, empyema, remote pancreato-renal transplant, thrombosed splenic vein, hemangiomata, pancreatic pseudocysts, splenic artery aneurysm, cholesterol embolism, splenic granuloma, congenital diaphragmatic hernia, rib exostosis, pancreatitis, Gaucher's disease, Wilson's disease, pheochromocytoma, afibrinogenemia and ruptured ectopic pregnancy. Conclusions Emergency physicians should be attuned to the fact that rupture of the spleen can occur in the absence of major trauma or previously diagnosed splenic disease. The occurrence of such a rupture is likely to be the manifesting complaint of an underlying disease. Furthermore, colonoscopy should be more widely documented as a cause of splenic rupture

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice : A multicentre cohort study

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads

Anales de Edafología y Agrobiología Tomo 47 Número 7-8

l. Suelos. Química. Estudio de los suelos de la depresión Guadix-Baza (Granada). II. Análisis de factores en modo R. Por A. lriarte Mayo, A . Pozzuoli y E. Barahona Fernández. Revisión del método de determinación automatizada de nitrógeno U. V. oxidable en extractos de suelos. Por J. A. Díez.-- Biología Consideraciones ecológicas y bioquímicas sobre la humificación en sabinares desarrollados sobre material calizo y gneísico. Por M. R. Rodríguez y F. Velasco.-- Génesis, Clasificación y Cartografía Suelos, geología y geomorfología en zonas erosionadas de la cuenca del Valdeamargos, depresión de Calatayud. Por M. A. Mulders, J. Slurink y J. Boixadera.-- Aplicación de la metodología de la cartografía básica a la comarca La Plana de Requena-Utiel (Valencia). Por R. Boluda Hernández, M. Moraleda Esteve, V. Andréu Pérez y J. Sánchez Díaz.-- Estudio de caracterización de minerales (fracción arena) en suelos gleicos de una zona semiárida. Por Mª P. García Rodríguez, J. Fortéza Bonnin, A. García Rodríguez y L. F. Lorenzo Martín, con la colaboración técnica de N. Najac Ballesteros.-- Clasificación de sectores ecológicos en la sierra del Negrete y Utiel (Valencia), utilizando el sensor thematic mapper del satélite Landsat-5. Por R. Boluda Hernández.-- Unidades de paisaje en el tercio norte del valle de Ayora (Valencia, España). Por J. A. Hernandez y J. L. Rubio.-- Suelos de la Isla de Gomera (1. Canarias). l. Vertiente septentrional. Características morfológicas, físico-químicas, mineralógicas, micromorfológicas, clasificación e interpretación. Por C. Jiménez Mendoza, M. L. Tejedor Salguero y A. Rodríguez Rodríguez.-- Suelos de la Isla de Gomera (1. Canarias). 11. Vertiente meridfonal. Ecología, Características morfológicas, físico-químicas, mineralógicas. micromorfológicas, clasificación e interpretación. Por C. Jiménez Mendoza, A. Rodrr'guez Rodríguez y M. L. Tejedor Salguero.--. Fertilidad Efecto de fertilizantes orgánicos sobre el cultivo de patatas y sobre las propiedades del suelo. Por J. A. Haroun Tabraue y E. Hernández.-- II. Biología Vegetal-Nutrición. Influencia del sistema de nutrición en la calidad de los frutos de tomate. l. Rendimientos, parámetros físicos, fracciones nitrogenadas, acidez y azúcares. Por F.J. López-Andréu, R . M. Esteban, E. Molla y O. Carpena.-- Influencia del sistema de nutrición en la calidad de los frutos de tomate. 11. Caro- tenoides, ácido ascórbico, sustancias pécticas y Flavonoides. Por F. J. López- Andréu, R. M. Esteban, E. Molla y O. Carpena.-- Fisiología Efecto de tres cultivares en el vigor de semillas de girasol. Por M. Torres y C. J. Martínez-Honduvilla.-- Agro biología Effect of qualities of irrigation water and N P K fertilizers on soil properties. Por P. Lal and R. Lal.-- Modelos estructurales condicionados por el arbolado en comunidades de diferente trofismo. Por A. Puerto, J. A. Garcra, M. D. Matías, J. A. Saldaña y C. Pérez.-- III. Trabajo recapitulativo. Relación entre el contenido de¡olifenoles y actividad fotosintéticas bajo radiación ultravioleta. PorJ. Baztan y RuanoPeer reviewe