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

Next-generation phylogenomics

Thanks to advances in next-generation technologies, genome sequences are now being generated at breadth (e.g. across environments) and depth (thousands of closely related strains, individuals or samples) unimaginable only a few years ago. Phylogenomics ? the study of evolutionary relationships based on comparative analysis of genome-scale data ? has so far been developed as industrial-scale molecular phylogenetics, proceeding in the two classical steps: multiple alignment of homologous sequences, followed by inference of a tree (or multiple trees). However, the algorithms typically employed for these steps scale poorly with number of sequences, such that for an increasing number of problems, high-quality phylogenomic analysis is (or soon will be) computationally infeasible. Moreover, next-generation data are often incomplete and error-prone, and analysis may be further complicated by genome rearrangement, gene fusion and deletion, lateral genetic transfer, and transcript variation. Here we argue that next-generation data require next-generation phylogenomics, including so-called alignment-free approaches

Long noncoding RNA as novel cancer diagnostic and effective therapeutic targets

© Springer Nature Singapore Pte Ltd. 2018. Recently large-scale genomic analyses have reported that the vast majority of somatic copy number alterations found in human cancers map to transcribed regions lacking protein-coding potential. This is not surprising considering that, although most of the human genome is transcribed into various classes of RNAs, less than 2% of them encodes for proteins. Among them, long noncoding RNAs (lncRNAs) constitute one of the most abundant classes of RNA, defined as RNA longer than 200 nucleotides not coding for proteins. Interestingly, lncRNAs are often expressed in a tissue- and cancer-specific manner, and their expression can be easily manipulated in vivo using antisense oligonucleotides (ASOs) making them attractive cancer-selective markers and therapeutic targets. Emerging biochemical evidence has revealed an incredible functional diversity for lncRNAs as they can recruit chromatin-modifying proteins, organize nuclear architecture, regulate mRNA stability and translation by competing with microRNA and RNA-binding proteins, and even alter protein localization and function. Accordingly, lncRNAs are emerging as important regulators of cancer initiation and progression. Here we discuss the role of lncRNAs in cancer and their potential as a new promising avenue for the advancement of cancer cell-specific therapeutic design.status: publishe