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Levi Garraway reflects on the three things that keep his compass true when the going gets tough.

Levi Garraway and colleagues report the identification of somatic mutations of RNF43, which encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling, in over 18% of colorectal adenocarcinomas and endometrial carcinomas.

Based on a virtual discussion during the American Association for Cancer Research (AACR) 2020 Annual Meeting, we asked several scientists actively working to improve representation of Black American populations in cancer research how they are addressing these issues.

Expression of more than 15,500 genes individually in a melanoma cell line treated with RAF, MEK, ERK or combined RAF–MEK inhibitors reveals a cyclic-AMP-dependent melanocytic signalling network associated with drug resistance; this may represent a novel therapeutic target for melanoma treatment.

Frank Stegmeier, Levi Garraway and colleagues apply a targeted mass spectrometry approach that measures level of histone modifications and identify a recurrent p.E1099K variant in NSD2 in acute lymphoblastic leukemia. When ectopically expressed in a cancer cell line, this variant promotes transformation.

Levi Garraway and colleagues report exome sequencing of 112 prostate adenocarcinomas and matched normal tissues. They identify novel recurrent mutations in several genes, including MED12, FOXA1 and SPOP. They find that tumors harboring SPOP mutations lack the TMPRSS2-ERG fusion or other ETS rearrangements, supporting the hypothesis that SPOP mutation is an early driver event in prostate tumorigenesis.

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.

Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.

In panels of cancer cell lines analysed for their response to drug libraries, some studies have proposed distinct pharmacological sensitivities for some cell lines while other studies have not seen the same trends; here the data in the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer are reassessed, and the authors report a stronger degree of concordance between the two data sets than that in a previous study.

Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care.

Whole-genome sequencing of 25 metastatic melanomas and matched germline DNA in humans reveals that the highest mutation load is associated with chronic sun exposure, and that the PREX2 gene is mutated in approximately 14 per cent of cases

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.

The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.

The Cancer Cell Line Encyclopedia presents the first results from a large-scale screen of some 947 cancer cell lines with 24 anticancer drugs, with the aim of identifying specific genomic alterations and gene expression profiles associated with selective sensitivity or resistance to potential therapeutic agents.

Prostate cancer is a common cause of male cancer-related deaths. Complete sequencing of prostate cancer genomes now reveals previously unknown balanced rearrangements. Single-nucleotide resolution afforded by sequencing indicates that complex rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

In cancer, the impact on cellular fitness of copy-number gains affecting collaterally-amplified genes remains poorly understood compared to oncogenes. Here, the authors integrate genomic data from tumours and cell lines and identify a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes, with potential therapeutic applications.

Genome-wide DNA methylation analysis of metastatic biopsies from patients with castration-resistant prostate cancer reveals marked epigenetic differences between samples with adenocarcinoma and neuroendocrine histologies.

Mutations inactivating ARID1A, a subunit of the chromatin remodeling SWI/SNF complex, have been identified in some human cancers. This study reveals that cancer cells with mutated ARID1A are dependent on the residual activity of the complex for proliferation and that even if concomitant alterations in the ARID1A homolog ARID1B can occur, loss of ARID1B activity confers a specific vulnerability to ARID1A-mutant cells that may in the future be explored for targeting purposes.

Optical pooled screening is enhanced by amplification of barcodes before in situ sequencing.

Microarray analyses have enabled tumours to be grouped on the basis of their genomic alterations rather than their tissue of origin. But does the identification of lineage-survival genes implicate lineage dependency (or lineage addiction) as a mechanism that is also affected by tumour genetic alterations?

This paper reports one of the largest breast cancer whole-exome and whole-genome sequencing efforts so far, identifying previously unknown recurrent mutations in CBFB, deletions of RUNX1 and recurrent MAGI1–AKT3 fusion; the fusion suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials.

Genomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.

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.

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

Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.