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

Resting energy expenditure, pulmonary inflammation, and genotype in the early course of cystic fibrosis

To further investigate the early course of cystic fibrosis (CF), specifically to examine factors contributing to energy imbalance, we examined resting energy expenditure (REE) (by indirect calorimetry) per unit body weight and metabolically active body cell mass (by total body potassium), in relation to CF genotype (by genomic DNA analysis), CF pancreatic phenotype, and markers of pulmonary inflammation (from bronchoalveolar ravage fluid). Eighteen subjects with presymptomatic CF who were less than 2 years of age (n=11, Delta F508/Delta F508 genotype; n=15, pancreatic insufficiency phenotype), identified by newborn screening, were compared with age-, sex-, and length-matched control subjects (n=13). Those with the Delta F508/Delta F508 genotype had significantly higher mean REE expressed per unit body weight (125%) and body cell mass (115%;

Immunoglobulin G (IgG) Expression in Human Umbilical Cord Endothelial Cells

Traditional views hold that immunoglobulin G (IgG) in the human umbilical cord is internalized by human umbilical endothelial cells for passive immunity. In this study, the protein and mRNA transcripts of IgG were found in the cytoplasm of human umbilical endothelial cells by immunohistochemistry, in situ hybridization, and reverse transcription PCR (RT-PCR). The essential enzymes for IgG synthesis and assembling, RAG1 (recombination activating gene 1), RAG2, and variable (V), diversity (D), and joining (J) segments for recombination of IgG, were also found in these cells by RT-PCR and real-time PCR. These results indicate that umbilical endothelial cells are capable of synthesizing IgG with properties similar to those of immune cells and that they may play additional roles besides lining the vessels and transporting IgG