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

Farmacoepidemiologia no Brasil: evolução e perspectivas Pharmacoepidemiology in Brazil: evolution and prospects

O presente trabalho apresenta o desenvolvimento da farmacoepidemiologia no Brasil. Enfatiza o papel dos programas de educação continuada em farmacologia coordenados pelo professor Carlos Lacaz, autor do primeiro livro brasileiro sobre doenças iatrogênicas. Ressalta o papel do programa de formação em farmácia clínica da Organização Pan-Americana de Saúde, onde vários profissionais brasileiros tiveram o primeiro contato com o Programa de farmacovigilância por Monitorização Intensiva Hospitalar. Refere também às primeiras teses de doutorado sobre medicamentos defendidas na Universidade de São Paulo. Relata a tentativa da Divisão de Medicamentos do Ministério da Saúde do Brasil de se direcionar para a farmacovigilância. Tece considerações sobre a I Oficina de Trabalho sobre medicamentos organizada pelas Secretarias Municipal e Estadual de Saúde de São Paulo. Enfatiza a criação da Sociedade Brasileira de Vigilância de Medicamentos, e sua importância como estimuladora da farmacoepidemiologia. Analisa o impulso do setor dinamizado pela implantação dos Centros de Informações de Medicamentos, no país. Conclui que já existem condições para se incrementar a pesquisa farmacoepidemiológica no Brasil.<br>This work recovers the historical development of pharmacoepidemiology in Brazil. The role played by the following events is particularly dealt with the influence of the pharmacological education programs coordinated by professor Carlos Lacaz, author of the first Brazilian textbook on iatrogenic diseases; the clinical pharmacy program offered by the Pan-American Health Organization, which provided a number of Brazilian professionals their first contact with the Program of Drug Surveillance by Intensive Hospital Monitoring; the first doctoral on drugs presented at São Paulo University; the attempt of the Division of Medicine of the Brazilian Health Ministry to include Pharmacovigilance among its more important aims. Also the founding of the Brazilian Association for Drug Surveillance are reported. Emphasis is also placed on the implementation of several Drug Information Centers in Brazil, and the new thrust thus provided to Drug Epidemiology. Finally, conclusions are drawn on the conditions for gathering efforts already available in universities and health service agencies nationwide in order to implement pharmacoepidemiological research in Brazil