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

A thin-film multichannel electrode for muscle recording and stimulation in neuroprosthetics applications

Objective. We propose, design and test a novel thin-film multichannel electrode that can be used for both recording from and stimulating a muscle in acute implants. Approach. The system is built on a substrate of polyimide and contains 12 recording and three stimulation sites made of platinum. The structure is 420 µm wide, 20 µm thick and embeds the recording and stimulation contacts on the two sides of the polyimide over an approximate length of 2 cm. We show representative applications in healthy individuals as well as tremor patients. The designed system was tested by a psychometric characterization of the stimulation contacts in six tremor patients and three healthy individuals determining the perception threshold and current limit as well as the success rate in discriminating elicited sensations (electrotactile feedback). Also, we investigated the possibility of using the intramuscular electrode for reducing tremor in one patient by electrical stimulation delivered with timing based on the electromyographic activity recorded with the same electrode. Main results. In the tremor patients, the current corresponding to the perception threshold and the current limit were 0.7  ±  0.2 and 1.4  ±  0.7 mA for the wrist flexor muscles and 0.4  ±  0.2 and 1.5  ±  0.7 mA for the extensors. In one patient, closed-loop stimulation resulted in a decrease of the tremor power  >50%. In healthy individuals the perception threshold and current limits were 0.9  ±  0.6 and 2.1  ±  0.6 mA for the extensor carpi radialis muscle. The subjects could distinguish four or six stimulation patterns (two or three stimulation sites  ×  two stimulation current amplitudes) with true positive rate  >80% (two subjects) and  >60% (one subject), respectively. Significance. The proposed electrode provides a compact multichannel interface for recording electromyogram and delivering electrical stimulation in applications such as neuroprostheses for tremor suppression and closed-loop myoelectric prostheses