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

Tradução e adaptação cultural para a língua portuguesa falada no Brasil da Canadian survey of mobilization of ICU patients

Este estudio tuvo como objetivo traducir y adaptar culturalmente el cuestionario Canadian survey of mobilization of intensive care unit patients al portugués de Brasil. Esteinstrumento evalúa a los profesionales de la unidad de cuidados intensivos (UCI) en cuanto al conocimiento sobre la movilización temprana (MT) y su importancia, las percepciones sobre lasbarreras y las prácticas de  rehabilitación con pacientes críticos.El protocolo incluyó las siguientes etapas: autorización y cesión de derechos de uso; traducción del instrumento al portugués brasileño; reconciliación; retrotraducción al idioma original; revisión y armonización de la retrotraducción; aprobación de la autora principal al cuestionario original; revisión de la versión al portugués; despliegue cognitivo; y reconciliación y preparación de la versión final. Debido a algunas diferencias conceptuales y culturales entre los dos países, se discutieron algunas dudas con la autora principal del instrumento, quien estuvo de acuerdo con los cambios sugeridos. En el despliegue cognitivo, los 10 profesionales seleccionados probaron la claridad, la comprensióny la aceptabilidad del cuestionario, y demostraron las dificultades de los contenidos. Numerosos entrevistados manifestaron que el instrumento suscita importantes reflexiones sobre las prácticas cotidianas y beneficios de llevar a cabo la MT. El cuestionario titulado Investigación en movilización de pacientes en unidades de cuidados intensivos: conocimientos, perspectivas y prácticas actuales está traducido y adaptado culturalmente al portuguésde Brasil, y puede ser utilizado para evaluar aspectos de MT por parte de profesionales que participan en este proceso en UCI de adultos y pediátrica. Se necesitarán estudios futuros que utilicen esta versión para verificar que el cuestionario proporciona la reproducibilidad y la validez de las medidas.Este estudo teve como objetivo traduzir e adaptar culturalmente o questionário Canadian survey of mobilization of intensive care unit patients para a língua portuguesa falada no Brasil. Este instrumento avalia profissionais de unidade de terapia intensiva (UTI) em relação aos conhecimentos sobre a mobilização precoce (MP) e sua importância, as percepções sobre barreiras e as práticas de reabilitação com o paciente crítico. O protocolo incluiu as etapas: autorização e cessão de direitos de uso; tradução do instrumento para a língua portuguesa;reconciliação; retrotradução para a língua original; revisão e harmonização da retrotradução; aprovação da autora principal do questionário original; revisão da versão em português; desdobramento cognitivo; e reconciliação e elaboração da versão final. Devido a algumas diferenças conceituais e culturais entre os dois países, algumas dúvidas foram discutidas com a autora principal do instrumento, a qual concordou com as alterações sugeridas. No desdobramento cognitivo, os 10 profissionais selecionados testaram a clareza, compreensão e aceitabilidade do questionário, e demonstraram suas dificuldades quanto ao conteúdo deste. Muitos entrevistados evidenciaram que o instrumento desperta reflexões importantes sobre as práticas diárias e os benefícios com a realização da MP. O questionário intitulado Pesquisa de mobilização de pacientes em unidade de terapia intensiva: conhecimento, perspectivas e práticas atuais encontra-se traduzido e adaptado culturalmente para a língua portuguesa falada no Brasil, podendo ser utilizado para avaliar aspectos da MP por profissionais que participam deste processo em UTIs adulto e pediátricas. Estudos futuros utilizando esta versão serão necessários para verificar se o questionário fornece medidas reprodutíveis e válidas.This study aimed to translate and culturally adapt the “Canadian survey of mobilization of intensive care unit patients” questionnaire to Brazilian Portuguese. This instrument evaluates intensive care unit (ICU) professionals’knowledge about early mobilization and its importance, their perceptions about barriers and rehabilitation practices with critically ill patients. The protocol includes the following steps: authorization and assignment of rights of use; translation of the instrument into Portuguese; reconciliation; back-translation to the original language; revision and harmonization of back-translation; approval from the main author of the original questionnaire; revision of the Portuguese version; cognitive debriefing; reconciliation; and preparation of the final version. Due to some conceptual and cultural differences between the two countries, some questions were discussed with the author of the original instrument, who agreed with the suggested  alterations. During cognitive debriefing, the 10 selected professionals tested the  questionnaire’s clarity, understanding, and acceptability, indicating any difficulties they had regarding its content. Many interviewees reported that the instrument raises important reflections on daily practices and thebenefits of early mobilization. The questionnaire entitled “Pesquisa de mobilização de pacientes em unidade de terapia intensiva: conhecimento, perspectivas e práticas atuais” was translated and culturally adapted to Brazilian Portuguese and can be usedto evaluate aspects of early mobilization by professionals whoparticipate in this process in adult and pediatric ICUs. Future studies using this version will be necessary to verify that the questionnaire provides  reproducible and valid measurements

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

Sex differences in oncogenic mutational processes

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.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.Peer reviewe

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

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

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.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 (VAFPeer reviewe

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

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.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

Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. 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), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing (vol 52, pg 331, 2020)

author correctio

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally