Search

Mark Rubin, Francesca Demichelis and colleagues study the evolution of urothelial carcinomas by performing whole-exome sequencing of tumors collected from patients before and after chemotherapy. They find marked within-patient tumor heterogeneity and increased mutations involved in integrin signaling pathways and APOBEC-induced mutation signatures after treatment.

Nature Biotechnology asks a selection of researchers about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

ETS gene fusions and PTEN loss are common events in prostate cancer, but their interactions are not well understood. A new study in mice suggests that overexpression of ETS in the setting of PTEN loss increases androgen receptor binding and restores androgen receptor transcriptional activity (pages 1023–1029).

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.

The immunopathological features of SARS-CoV-2 infection in the lungs remain unclear. Here, the authors provide a comprehensive characterization of post mortem lung tissues of COVID-19 patients and find two distinct patterns characterized by differential expression of interferon stimulated genes (ISGs), which correlate to viral loads, cytokines, lung damage and time of hospitalization, suggesting ISG profiles to mark disease progression

Transcription-replication conflicts (TRCs) promote tumor aggressiveness by affecting genome stability. Here, the authors identify ANP32E as driver of TRCs in breast cancer, causing R-loop accumulation and genomic instability, which elicit vulnerability to ATR inhibition.

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.

A newly published study used whole-genome sequencing of multiple prostate tumour foci from several patients with intermediate-risk prostate cancer to track evolutionary patterns and delineate the marked intrapatient molecular heterogeneity of this disease. Their findings have potential implications for the development of clinical prognostic and predictive biomarkers.

Prostate cancer is a heterogeneous disease, and many cases show somatic mutations of SPOP. Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response.

While CRISPR-Cas9 is a powerful technology, it’sin vivoapplication can be limited by unwanted off-target editing events. Here the authors present SLiCES, a self-limiting Cas9 circuit to enhance editing by preventing residual nuclease activity.

Benign prostatic hyperplasia (BPH) is one of the most common diseases affecting aging men with limited therapeutic options. In this study, the authors describe the molecular characterization of BPH performing genomic, transcriptomic and epigenetic analysis of 18 BPH cases.

Bladder cancer heterogeneity can limit treatment efficacy in individual patients. Here, the authors use patient derived organoids to develop a drug screening pipeline and identify markers of treatment response.

The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation.

One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

There are few available models to study neuroendocrine prostate cancer. Here they develop and characterize patient derived organoids from metastatic lesions, use these models to show the role of EZH2 in driving neuroendocrine phenotype, and perform high throughput organoid screening to identify therapeutic drug combinations.

Evolved SpCas9 variant evoCas9 has improved specificity and retains near wild-type on-target activity.

Genomic analyses of cancer genomes have largely focused on mutations in protein-coding regions, but the functional importance of alterations to non-coding regions is becoming increasingly appreciated through whole-genome sequencing. This Review discusses our current understanding of non-coding sequence variants in cancer — both somatic mutations and germline variants, and their interplay — including their identification, computational and experimental evidence for functional impact, and their diverse mechanisms of action for dysregulating coding genes and non-coding RNAs.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors.

The Microarray Quality Control consortium pitted 36 teams against each other to evaluate methods for creating genomic classifiers, computational tools for interpreting gene expression profiles. The performance of the classifiers on blinded validation data—and metadata on the analytic methods—reveal the challenges facing the field.

Meta-analysis of exome sequencing data identifies new recurrently mutated driver genes for prostate cancer. Comparison of primary and metastatic tumors further identifies genomic markers for advanced prostate cancer that may inform risk stratification.

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.

Matteo Benelli et al. present Rocker-meth, a new Hidden Markov Model (HMM)-based method, to robustly identify differentially methylated regions (DMRs). They use Rocker-meth to analyse more than 6000 methylation profiles across 14 cancer types, providing a catalog of tumor-specific and shared DMRs.

Although cancer genetics analyses have often focused on individual mutations of classic cancer genes, a wealth of cancer sequencing data are allowing a more comprehensive understanding of the cumulative effects of mutations genome-wide. In this Perspective article, the authors propose how the burden of different types of mutation — from point mutations to large-scale chromosomal aberrations — has distinct and compensatory effects on tumour fitness and selection during different stages of cancer evolution.

Rubin and colleagues discuss the origin and evolution of poorly differentiated neuroendocrine tumors, and highlight potential new therapeutic strategies.

In prostate cancer, the oncogenicity of transcription factor ERG is mediated, in part, by competition with another member of the ETS family, ERF.