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Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6-RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair.

A large integrated genome and transcriptome analysis of colorectal cancer identifies prognostic mutations and expression subtypes.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Joint analysis of new and previously published sequencing data for primary and metastatic prostate cancers identifies new candidate driver mutations and provides insights into disease progression and potential drug targets.

Spatially variable surface-elevation changes across 40 global deltas using interferometric synthetic aperture radar are reported.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure

In this study, the authors describe how light shapes a long-term threat avoidance behavior via a visual circuit linking the eye with the limbic system in mice.

Whole-genome and targeted sequencing of multiple sections of each of 50 tumors reveals varying degrees of subclonal diversification and genomic heterogeneity.

Rajshekar et al. show that a hierarchy of affinities layers pericentromeric heterochromatin around nucleoli, with the RNA helicase Pitchoune (DDX18) acting as a key dual-affinity linker in Drosophila melanogaster.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Electron-microscopy data are used to reconstruct the neurons that make up the anterior visual pathway in the Drosophila brain, providing insight into how visual features are encoded to guide navigation.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.

Examination of archaeological pottery residues and modern genes suggest that environmental conditions, subsistence economics and pathogen exposure may explain selection for lactase persistence better than prehistoric consumption of milk.

The COMPASS trial is a prospective observational study seeking to establish biomarkers in advanced pancreatic cancer through in-depth profiling prior to commencing chemotherapy. Here, the authors report the final data for the complete cohort of 268 patients enrolled in the COMPASS trial.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

A study of breast cancers shows that the number of somatic mutations in each varies markedly and is strongly correlated with age at diagnosis and cancer histological grade.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

A modeling approach to assess the global risk of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions identifies ten priority African countries for surveillance and could inform malaria control policies.

Joana Carlevaro-Fita, Andrés Lanzós et al. present the Cancer LncRNA Census (CLC), a manually curated dataset of 122 long noncoding RNAs (lncRNAs) with experimentally-validated functions in cancer based on data from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. CLC lncRNAs have unique gene features, and a number display evidence for cancer-driving functions that are conserved from humans to mice.

In this journal club, Lucy Thorne discusses a paper that compares pandemic and non-pandemic HIV and shows that the ability of pandemic HIV to effectively evade the host’s innate immune response is a key factor in its pandemic potential.

Two papers by Kather and colleagues and Gerstung and colleagues develop workflows to predict a wide range of molecular alterations from pan-cancer digital pathology slides.

The sensitivity of mesothelioma to the treatment of immune checkpoint blockade remains elusive. Here this group reports a double blind, placebo-controlled, randomized phase III trial of PD1 inhibitor (Nivolumab) on 332 patients with relapsed mesothelioma, and to uncover determinants of efficacy.

Aromatase inhibitors are used to treat oestrogen receptor positive breast cancers but the molecular basis for the response of patients is unclear. Here, the authors use samples from an aromatase inhibitor clinical trial and show that tumours from poor responders have more mutations than good responders and also more frequently harbour p53 mutations.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.