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

Surgical treatment of premature sagittal synostosis Tratamento cirúrgico da fusão prematura da sutura sagital

A series of 50 consecutive children with premature sagittal synostosis is reported. All were treated surgically; 43 were male, 47 were leukodermic and two are siblings. In the pre-operative examination, the head shape, skull measurements and radiologic findings were evaluated; 38 children were operated on before six months of age and 12 of them, between six and 12 months of age. The surgical technique used was a wide biparietal craniectomy. Blood transfusions were occasional, being necessary for only six (12%) children. The children were admitted at the day of surgery and discharged between the second and the third post-operative day. No local or general complications were observed and no one died. The aesthetic result was considered good. The altered skull measurements before surgery reached normalization as far as the end of the first year after the treatment. It may be concluded that wide biparietal craniectomy is a procedure of great effectiveness in the treatment of the premature fusion of the sagittal suture.<br>É apresentada uma série de 50 crianças com fusão isolada e prematura da sutura sagital, tratadas cirurgicamente; 43 eram do sexo masculino, 47 leucodérmicas e duas irmãs. No pré-operatório foram avaliados o formato da cabeça, medidas do crânio e medidas radiológicas, 38 crianças foram operadas antes dos 6 meses de idade e 12 entre os 6 e 12 meses. A técnica cirúrgica usada foi a craniectomia parcial, ampla e biparietal. A transfusão sanguínea foi eventual, sendo necessária em somente 6 crianças (12%). As crianças foram admitidas no dia da cirurgia e receberam alta entre o segundo e terceiro dia após a cirurgia. Não foram observadas complicações locais ou gerais e não houve óbito. O resultado estético final foi considerado bom; as medidas do crânio, alteradas antes da cirurgia, se normalizaram até um ano após o tratamento. Conclui-se que a craniectomia parcial, ampla e biparietal é eficiente no tratamento da fusão isolada e prematura da sutura sagital, até o primeiro ano de vida