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Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.

A panel of experts discusses the challenge of translating findings from current mouse models to the clinic.

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.

Genomic genetically engineered mouse models (GEMMs) have provided a wealth of information about the genes and factors involved in tumour progression. However, various limitations exist for such models, particularly for preclinical drug development. So, what improvements can the non-germline GEMMs offer?

A genome-wide screen has identified a frequent region of amplification on chromosome 5p13 in a number of cancer types. Functional studies now identify a protein localized to the Golgi apparatus, GOLPH3, as a novel oncogene affected by this amplification which can transform cells in vitro and lead to tumour formation in vivo. GOLPH3 overexpression activates the mTOR signalling pathway and renders cancer cells sensitive to the drug rapamycin.

Next-generation sequencing has allowed an unprecedented genomic characterization of diverse cancer types. This Review describes our latest understanding of cancer genomes, including methods to interpret the mutation data, and the emerging biological and clinical implications.

Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long-term regenerative capacity. Here, and in two accompanying studies, it is shown that the tumour suppressor Lkb1 has a crucial role in maintaining energy homeostasis in haematopoietic cells.

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

Integrative analysis of copy number and gene expression in 2,000 primary breast tumours with long-term clinical follow-up revealed putative cis-acting driver genes, novel subgroups and trans-acting aberration hotspots that modulate subgroup-specific gene networks.

Here, the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person are sequenced, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The data provide insight into the causes of tumour formation and the development of the cancer genome, with the dominant mutational signature reflecting DNA damage due to ultraviolet light exposure.

Here it is shown that telomere dysfunction drives metabolic and mitochondrial compromise. Mice with dysfunctional telomeres activate p53, which in turn represses PGC-1α and PGC-1β, master regulators of metabolic and mitochondrial processes. This results in reduced mitochondrial mass, mitochondrial dysfunction and reduced ATP generation, impaired gluconeogenesis, cariomyopathy and increased reactive oxygen species. This telomere–p53–PGC pathway shows how telomere dysfunction may compromise organ function and contribute to age-related disorders.

The ‘collateral’ homozygous deletion of essential redundant housekeeping genes in cancer genomes is shown to confer therapeutic vulnerability on cancer cells with the deletion, without affecting genomically intact normal non-cancerous cells, suggesting new therapeutic opportunities.

With a comprehensive analysis of sequencing data, DNA copy number, gene expression and DNA methylation in a large number of human glioblastomas, The Cancer Genome Atlas project initiative provides a broad overview of the genes and pathways that are altered in this cancer type.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

The Cancer Genome Atlas Research Network report integrated genomic and molecular analyses of 164 squamous cell carcinomas and adenocarcinomas of the oesophagus; they find genomic and molecular features that differentiate squamous and adenocarcinomas of the oesophagus, and strong similarities between oesophageal adenocarcinomas and the chromosomally unstable variant of gastric adenocarcinoma, suggesting that gastroesophageal adenocarcinoma is a single disease entity.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity.

Analysis of glioblastoma samples and derived neurospheres and xenografts shows that chromosomal and extrachromosomal alterations often display divergent inheritance patterns during cell culture and xenografting.

Complex genomic alterations segregate melanoma into different molecular subsets, but for most subsets it is unclear whether they drive a distinct clinical behaviour. Here, the authors use gene-expression data from melanoma patients to search for outlier genes that correlate with survival and identify that MTSS1 is associated with metastasis.

A mouse lymphoma model that shows a similar level of genomic instability generally seen in human cancer has been created. In a comparative genomics approach, recurrent genetic alterations found in this model are used as a filter to identify overlapping alterations in human T-cell acute lymphoblastic lymphomas, including in the FBXW7 and NOTCH genes.

The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic target is identified in most of the samples studied.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

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.

Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

In a mouse model of prostate cancer it is found that that the TGF-β signalling pathway limits tumour progression and metastasis. Using markers of this pathway and other biologically relevant factors, a four-gene signature is identified that is associated with poorer clinical outcome and metastatic progression in several prostate cancer cohorts, especially in combination with other clinical parameters. This signature may prove useful for the development of a better prognostic test for those cases of prostate cancer in which deciding on the right treatment regime while avoiding over-treatment constitutes an important clinical challenge.

One reason for the high failure rate of experimental cancer therapies is that mouse tumor models do not accurately predict the behavior of human cancers. Zhou et al. provide more realistic models by generating chimeric mice bearing drug-inducible, tissue-specific oncogenes.

NRAS-driven melanomas have limited therapeutic options. Combining genetically engineered models and oncogenic signaling inhibitors with rational systems-biology approaches, the authors compare the effects of genetic extinction of NRAS to that of chemical pathway inhibition targeting downstream MEK. The differences provide actionable targets by revealing that NRAS signaling operates as a gated output and that MEK inhibition, although inducing apoptosis, is not able to achieve further inhibition of NRAS-induced outputs such as cell-cycle progression. A combination of MEK and CDK4 inhibitors provides a more complete inhibition of NRAS signaling and a more effective antitumor effect in vivo.

Depletion of Smarcb1 activates the Myc network of signalling cascades, increasing protein metabolism and activation of survival pathways allowing highly aggressive Kras-independent pancreatic cancer cells to develop.

This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations and HPV types.