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In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Understanding the immunological underpinnings of long-term survival in cancer is of high interest. Here, authors dissect the immune parameters of multiple myeloma long-term survivors following a single line of therapy longitudinally, and find sustained changes, including inflammation and impaired immune function.

Analyses of genomes from 914 children, adolescents, and young adults provide a comprehensive resource of genomic alterations across a spectrum of common childhood cancers.

Reiner Siebert and colleagues report whole-genome, whole-exome and transcriptome sequencing of Burkitt lymphomas. They identify recurrent mutations in several genes not previously known to be mutated in Burkitt lymphoma, including ID3, FBXO11, DDX3X and RHOA.

Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes.

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.

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.

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.

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.

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.

The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Zhou et al. investigate the molecular events that follow neoadjuvant treatment in PDAC patients, explore signatures of heterogeneous response and persister phenotypes, identify a CYP3A link to resistance and suggest that it is useful in predicting response.

A benchmarking competition improves tools that predict how regulatory regions control gene expression.

Somatic evolutionary analysis of neuroblastoma, a pediatric tumor, proposes a common fetal time of origin. Notably, high-risk tumors exhibit early genomic instability and prolonged evolution, and this evolutionary duration predicts clinical outcomes.

Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.

The shattering of chromosomes is a dramatic early event in tumourigenesis and is termed chromothripsis. Here, the authors examine chromothripsis across 28 tumour types and show that 49% of cancers exhibit features of chromothripsis.

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.

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.

The thymus generates all T cells, including those that underly autoimmune diseases. Here, using deep sequencing, the authors profile human medullary thymic epithelial cells and establish a web portal to query their transcriptome, which may serve as a tool to help identify the drivers of autoimmunity.

Cancer genetics has benefited from the advent of next generation sequencing, yet a comparison of sequencing and analysis techniques is lacking. Here, the authors sequence a normal-tumour pair and perform data analysis at multiple institutes and highlight some of the pitfalls associated with the different methods.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.

Roider et al. combine scRNA-seq and transcriptome-informed flow cytometry, and uncover transcriptionally different malignant subclones with distinct drug responses and T-cell profiles in B-cell non-Hodgkin lymphoma.

Cutaneous squamous cell carcinoma (cSCC) is a skin cancer that normally progresses from UV-induced actinic keratosis (AK). Here, the authors investigate the epigenomics of cSCC and highlight two distinct subclasses of AK and cSCC originating from distinct keratinocyte differentiation stages.

The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients.

T cells develop from thymic precursor cells that are constantly replaced with newly arriving bone marrow progenitor cells, and the ‘old’ and ‘new’ cells are shown here to compete; in the absence of cell competition, when the influx of new bone marrow progenitor cells is blocked, the old cells acquire the ability to self-renew and eventually become transformed, leading to the development of a form of leukaemia.

Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation.