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 Non-Abelian Exponentiation theorem for multiple Wilson lines

We study the structure of soft gluon corrections to multi-leg scattering amplitudes in a non-Abelian gauge theory by analysing the corresponding product of semi-infinite Wilson lines. We prove that diagrams exponentiate such that the colour factors in the exponent are fully connected. This completes the generalisation of the non-Abelian exponentiation theorem, previously proven in the case of a Wilson loop, to the case of multiple Wilson lines in arbitrary representations of the colour group. Our proof is based on the replica trick in conjunction with a new formalism where multiple emissions from a Wilson line are described by effective vertices, each having a connected colour factor. The exponent consists of connected graphs made out of these vertices. We show that this readily provides a general colour basis for webs. We further discuss the kinematic combinations that accompany each connected colour factor, and explicitly catalogue all three-loop examples, as necessary for a direct computation of the soft anomalous dimension at this order.Comment: v2 - typos corrected, references added, to appear in JHEP; 57 pages, 21 figures. v3 - correction in Table 2 and Appendix A.2.5; updates references; 57 pages, 21 figure

Considerations for structure-based drug design targeting HIV-1 reverse transcriptase

© Springer Science+Business Media Dordrecht 2015 HIV-1 reverse transcriptase (RT) copies the viral single-stranded RNAgenome into a double-stranded DNA version, and is a central target for anti-AIDStherapeutics. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleosideinhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have beendetermined in complexes with substrates and/or inhibitors, and the structures haverevealed different conformational and functional states of the enzyme. Rilpivirineand etravirine, two NNRTI drugs with high potency against common resistantvariants, were discovered and developed through a multidisciplinary structure-baseddrug design effort. The resilience of rilpivirine and etravirine to resistance mutationsresults from the structural flexibility and compactness of these drugs. Recentinsights into mechanisms of inhibition by the allosteric NNRTIs include (i) dynamicsliding of RT/NNRTI complexes along template-primers and (ii) displacement of theRT primer grip that repositions the 30-primer terminus away from the polymeraseactive site.status: publishe