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

The Free Triiodothyronine, Gamma-Glutamyl Transpeptidase and Spontaneous Bacterial Peritonitis Index: A Novel Model for Predicting 1-Year Mortality in Patients with HBV-Related Hepatic Encephalopathy

Lin Lin,1,2,&ast; Ze-yu Huang,1,&ast; Kai Liu,1,3 Xue-cheng Tong,1,3 Zhi-xin Zhang,4 Yuan Xue1,3 1Institute of Hepatology, The Third People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 2Department of Pharmacy, The Third People’s Hospital of Changzhou, Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of China; 3Department of Infectious Diseases, The Third People’s Hospital of Changzhou, Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of China; 4Department of Pulmonary Diseases, The Third People’s Hospital of Changzhou, Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuan Xue; Zhi-xin Zhang, Email [email protected]; [email protected] and Aims: Hepatic encephalopathy (HE) is characterized by neuropsychiatric manifestations in patients with decompensated cirrhosis (DC) and/or liver failure. This study aimed to investigate the predictive value of thyroid hormone in patients with HE.Methods: Patients with DC and HE were enrolled, and multivariate logistic analysis was conducted to analyze the risk factors for 1-year mortality.Results: Among the 81 patients with HBV-related DC and HE, 9 (11.1%) died within 3 months, and 15 (18.5%) died within the first year. More patients with FT3 < 3.5pmol/L had ascites (33.3% vs 8.9%, P< 0.01) and higher model for end-stage liver disease (MELD) (Z=3.669, P< 0.01). Additionally, free triiodothyronine (FT3) levels were lower in the non-survivor group (P< 0.01). FT3 exhibited a negative correlation with international normalized ratio and MELD (both P< 0.05). Multivariate analysis revealed that FT3, gamma-glutamyl transpeptidase (GGT), and spontaneous bacterial peritonitis (SBP) were independent risk factors for 1-year mortality of HE. A new model incorporating FT3, GTT, and SBP demonstrated superiority to MELD based on the AUROC (0.9 and 0.752, P=0.04).Conclusion: Low FT3, but not thyroid-stimulating hormone and free tetraiodothyronine, was identified as an independent risk factor for 1-year mortality in patients with DC and HE. The newly proposed prognostic model, which includes FT3, GTT, and SBP, holds significant predictive value.Keywords: hepatic encephalopathy, free triiodothyronine, model for end-stage liver disease, gamma-glutamyl transpeptidase, mortalit