Cancer genomics — from bench to bedside
The advent of massively parallel sequencing technologies has driven the analysis of cancer genomes at an unprecedented resolution. Sequence data from thousands of patients highlight the distinct sets of driver mutations among patients with the same cancer tissue type, and single-cell sequencing technologies have revealed heterogeneity within the subclones of single tumours as they evolve. Identifying and characterizing these mutations and their diversity is essential for the development of personalized therapies. Next-generation sequencing technologies have also been applied to study the epigenomes and transcriptomes of cancer, thus paving the way for an integrated understanding of cancer pathology.
This collection, which includes articles from Nature Reviews Genetics, Nature Reviews Clinical Oncology and Nature Reviews Cancer, showcases how cancer genomics has informed our understanding of cancer pathogenesis, unravelled potential future therapeutic targets and driven advances that are starting to translate into the clinic. This resource provides a comprehensive bench-to-bedside overview of cancer genomics, which will be useful to researchers and clinicians alike.
Highlights & News
Two papers report that mutations in calreticulin occur in most patients with JAK2− essential thrombocythemia and primary myelofibrosis, which are two common myeloproliferative neoplasms.
Jesse Boehm and Todd Golub call for an international effort to establish >10,000 cancer cell line models as a community resource. Cancer cell line factories will facilitate the creation of a cancer dependency map, connecting cancer genomics to therapeutic dependencies.
Over the past decade, genetic testing for rare inherited mutations, such as BRCA1 and BRCA2 mutations, has been successfully incorporated into clinical practice. Next-generation sequencing of cancer-susceptibility genes and entire tumour genomes has transformed cancer care and prevention. The discoveries of new cancer syndromes have raised exciting opportunities and potential liabilities for cancer-care providers seeking to incorporate genomic approaches into preventive oncology practice.
Three studies demonstrate that adenosine-to-inosine RNA editing introduces transcriptome diversity in tumours from a range of cancer types and show that this diversity is both functionally important and clinically relevant.
Reviews & Perspectives
Although cancer genome sequencing is becoming routine in cancer research, cancer transcriptome profiling through methods such as RNA sequencing (RNA-seq) provides information not only on mutations but also on their functional cellular consequences. This Review discusses how technical and analytical advances in cancer transcriptomics have provided various clinically valuable insights into gene expression signatures, driver gene prioritization, cancer microenvironments, immuno-oncology and prognostic biomarkers.
Cancer immunotherapies are promising strategies for cancer treatment. However, their optimized use will require a comprehensive understanding of the diverse cell types, antigens and genetic variants (both germline and somatic) that comprise the tumour–immune system interface. This Review discusses various bioinformatics tools that process multi-level omics data for insights into tumour–immune cell interactions.
The abundance and heterogeneity of mutations in cancer create challenges for understanding their effects, but such functional characterization will be crucial for optimizing clinical care. In this Review, the authors discuss diverse computational tools and systems biology experimental strategies for elucidating the functional effects of cancer mutations, including consequences on gene regulation, protein structure and local and global perturbations of molecular interaction networks.
The use of phylogenetics in cancer genomics is increasing owing to a growing appreciation of the importance of evolutionary theory to cancer progression. The authors provide guidance on the design and analysis of tumour phylogeny studies by surveying the range of phylogenetic methods and tools available to the cancer researcher and discussing their key applications and the unsolved problems in the field.
This Analysis article discusses characterization of the kinome in human cancers through genomic, proteomic and functional genomic analyses. In particular, it presents an analysis of cancer genomic data to derive a new census of protein kinase cancer drivers.
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.
Somatic genetic mosaicism has been demonstrated in many tissues, leading to interactions between functionally diverse cell populations that could contribute to homeostasis ('clonal health') or influence disease states. These authors argue that embryonic somatic mosaicism can contribute to adult cancers.
The evolution of genes is influenced by regional variation in mutation rates (RViMR). Chromatin organization affects RViMR, although the correlation between chromatin state and mutation types and rates is complex. This Review describes recent research on RViMR and chromatin organization, and the emerging findings from investigations of both germline and somatic mutations.
Most cancer genomics studies have focused on identifying the most important somatic mutations ('major drivers') that promote tumour growth. However, many cancer-associated mutations might instead have relatively weak tumour-promoting effects. This Opinion article highlights the existence of these mutations (termed 'mini drivers') and the functional effects that they might have.
The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The authors discuss the limitations, including the identification of driver events, and the possible solutions to the application of precision medicine in the management of patients with metastatic disease, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.
Recent analyses of cancer genomes have revealed the occurrence of mutation patterns, which indicate their source. This Review discusses what we have learned, and what is yet to learn, from these data and how our current understanding of cancer mutations fits into our understanding of tumorigenesis and tumour progression.
The landscape of translational oncology has shifted dramatically over the past 10 years, characterized by the introduction of more-sophisticated molecular tools into the clinic and advances are being employed in genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. The authors review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years.
Various small molecules, including numerous anticancer agents, act by targeting DNA or protein components of chromatin. This Review describes how various complementary technologies use high-throughput sequencing to delineate drug responses, from identifying the genomic binding sites of drugs or their targets, to the ensuing changes to chromatin states and gene expression. These insights should facilitate the rational use of these therapies.
The field of cancer genomics has been transformed by recent advances in sequencing and the development of new computational methods. This Review outlines the available cancer genomics software and describes recent insights gained from the application of these tools.
Mutagenic processes leave characteristic imprints on the cancer genome that can help to identify the underlying DNA damaging components as well as DNA repair and replicative pathways that are active or disrupted. This Review discusses these mutational signatures according to different classes of mutations and summarizes how different components contribute mechanistically to produce each signature type.
Systems biology approaches are beginning to provide information that will enable a more complete view of how the genomic and epigenetic aberrations in cancer cells can alter the homeostasis of signalling networks within the tumour and surrounding microenvironment, both at the organ and organism level. This Review describes the potential of these systems-based approaches and how they are becoming vital for the development and implementation of effective drug discovery and personalized cancer therapy.
In this Review, Jeff Shrager and Marty Tenenbaum describe the latest generation of Precision Oncology, and the different ways to keep refining it. In Precision Oncology 3.0, each treatment event provides the chance to learn from it so that such treatment can be applied to other patients with similar characteristics without facing the difficult economic and structural challenges of a clinical trial.
Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer
There is an increasing realization of epigenetic dysregulation in cancer, which comprises both the mutation of genes encoding epigenetic regulators and the broader disruptions to chromatin states of the epigenome. This Review discusses our latest understanding of these phenomena, their convergence and the implications for cancer biology and therapeutics.
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.
This Review discusses the considerations for designing cancer genome-sequencing studies to fulfil different study aims, such as detecting recurrent mutations or assessing clonal evolution. For example, the cohort type and depth of sequencing can influence the downstream analysis.
Many cancers, particularly those that arise in childhood, have a hereditary component. In this Perspectives article, the authors provide their views on how the increased adoption of high-throughput DNA sequencing technologies, which produce vast genetic data that is not necessarily limited to known cancer-susceptibility loci, and cancer surveillance strategies are influencing the clinical management of familial cancer. Important ethical issues relating to genetic counselling and disclosure of genetic information on disease susceptibility are discussed, and strategies for approaching these ethical dilemmas are proposed.
A key challenge in oncology is obtaining drugs predicted to be beneficial based on the patient's tumour profile. One solution is creation of a national facilitated access programme and registry for off-label use of targeted anti-cancer drugs. Schilsky discusses several key elements of implementing personalized cancer care services in an oncology practice setting and offers solutions to some of the obstacles of making personalized medicine available to many patients.
The development and implementation of more effective genome analysis technologies has enabled substantial improvements in our understanding of the genomic changes that take place in patients with acute lymphoblastic leukaemia (ALL). This Review provides a detailed summary of advances in our understanding of the genomics of ALL, and describes how these advances might lead to improved patient outcomes.
Genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This Opinion article proposes that this limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies.
The CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated 9) system provides many avenues for improving how we generate models of cancer. This system has numerous uses, including providing a means to understand the importance of genetic alterations as a tumour evolves, and CRISPR–Cas9 may potentially constitute a therapeutic strategy in the future.
Combined analyses of molecular data, such as DNA copy-number alteration, mRNA and protein expression, point to biological functions and molecular pathways being deregulated in multiple cancers. The integrative genomics methodologies that are used to interpret these data can seem daunting, but are discussed in this Review in simplistic terms and in the context of their use in cancer research.
Among rodent species, there is a wide diversity in lifespans and cancer susceptibilities, which makes comparative studies of rodents an attractive strategy for identifying molecular mechanisms that underlie ageing and cancer. This Review describes the various biological insights provided by comparative rodent genomics, including those from whole-genome sequencing of long-lived and highly cancer-resistant species. Such progress has potential implications for understanding and modulating human disease.
Cardiotoxic effects of chemotherapy can occur in various different ways depending upon the type of chemotherapy used and various patient characteristics. In this Review, the authors describe the established cardiotoxic effects of anthracyclines and HER2 inhibitors, and describe a systems medicine approach that might enable the optimal management of acute and chronic cardiotoxcities in patients who are receiving, or have received, these therapies.
Chromosome instability (CIN) is gaining increasing interest as a central process in cancer, and is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. In this Review, the authors review the literature published since 2000 that support the hypothesis that aneuploidy is a predictor of a poor prognosis in patients with cancer, focusing on the evidence from studies of seven common epithelial cancer types that performed multivariate analyses. The implications of ploidy analysis with regard to our theoretical understanding of the role of CIN in carcinogenesis, as well as its prognostic use in the clinic, are discussed.