Research to develop targeted therapies for paediatric medulloblastoma is inevitably performed in patient samples or animal models that have not received previous treatment, whereas testing of novel agents in the clinic when tumours recur involves patients who have previously undergone surgical resection, chemotherapy and radiotherapy. It is not known whether the recurrent tumour is biologically and genetically similar to the tumour at diagnosis. Michael Taylor and colleagues have developed and validated a 'humanized' mouse model of recurrent medulloblastoma and perform a direct genetic comparison between primary and recurrent tumours. They find that recurrent tumours have undergone drastic genetic changes due to clonal selection, hence many potential therapeutic targets identified in the primary tumor are unlikely to be present in a recurrent tumour. This information suggests ways in which future treatment strategies might be improved.
Tumour progression is driven by a process of clonal evolution. The importance of this process has been increasingly recognized over the past decade: tumour heterogeneity, the major cause of therapeutic resistance to antitumour agents, results from the genetic, epigenetic and microenvironmental selective pressure that tumour cells undergo during cancer progression.
In this collection, the cancer editorial community of the Nature journals presents the most recently published articles on cancer evolution. The topic is discussed from different complementary angles (preclinical, translational and clinical), and across a broad range of tumour types. This collection has been produced with exclusive support from EMD Serono. The collection content is editorially independent and the sole responsibility of Springer Nature.
Oncogenic driver mutations are identified in single cells by a transposon-based sequencing method.
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.
Nicholas Navin and colleagues use highly multiplexed single-nucleus sequencing to investigate DNA copy number evolution in patients with triple-negative breast cancer. Their data suggest that most copy number alterations are acquired at the earliest stages of tumor evolution in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.
Genome-wide transposon screening and quantitative insertion site sequencing for cancer gene discovery in mice
Friedrich et al. describe their toolkit for transposon-based insertional mutagenesis in mice for discovering cancer genes. Genome-wide transposon insertion sites are identified, mapped and quantified using QiSeq.
Although most cancers exhibit some degree of intratumour heterogeneity, we are far from understanding the dynamics that operate among subclonal populations within tumours. This Review discusses the growing evidence that cooperative behaviour of tumour subclones can influence disease progression.
Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer
Genomic analysis of a single metastasis informs about the oncogenic—and potentially druggable—genomic alterations present in other tumors within the same man with metastatic prostate cancer.
The molecularly targeted therapy paradigm has led to improvements in the management of patients with cancer. Responses to targeted therapies are, however, mostly short-lived, owing to inherent or acquired resistance, which in most cases relates to the outgrowth of pre-existent rare subclones harbouring resistance mutations. Our current understanding of this concept is reviewed herein; how knowledge of pre-existing resistance mechanism obtained through the use of ultra-sensitive sensitive DNA-sequencing assays might be best exploited to improve personalized medicine is discussed.
Although known to induce cellular senescence, an important tumour suppressor mechanism, mutation of CDKN1A — the gene encoding p21 (also known as WAF1 or CIP1) — is rare in human cancers. Now, a study reports a previously unappreciated oncogenic effect of p21 overexpression that shapes cancer genome evolution through induction of replication stress.
Disruption to the epigenome is increasingly appreciated as a major contributor to the development of cancer. The authors discuss how conceptualizing genes affecting the epigenome as epigenetic modulators, epigenetic modifiers or epigenetic mediators provides a valuable framework for understanding diverse aspects of the causes and consequences of epigenome alteration in cancer.
This single nucleus-targeted sequencing approach incorporates multiplexing and targeted capture for efficient high-throughput detection of genome variants. The protocol will be particularly useful for studying rare cells and complex cell populations.
Xenograft transplantation of primary human cancer cells into mice provides valuable models in which to study mechanisms underlying tumorigenesis, drug response and resistance. This study demonstrates that clonal evolution resembling that seen in human tumours also occurs on engraftment and during subsequent passaging of breast tumours in immunodeficient mice. In addition, similar clonal expansion patterns emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. These findings suggest that patient-derived xenografts may be useful for studying patient-specific tumour characteristics such as the response to drugs tailored to specific genomic alterations.
In the past 5 years, results from large-scale whole-exome sequencing studies have brought new insight into the clonal heterogeneity and evolution of multiple myeloma, a genetically complex disease. Herein, the authors describe the driver gene alterations and sequential acquisition of the main genomic aberrations involved in this disease, with a focus on the clonal heterogeneity of multiple myeloma and its clinical implications.
A recently emerged infectious cancer has caused the near extinction of the Tasmanian devil, but some populations persist. Here, Epstein et al. provide evidence for possible resistance via rapid evolution in two genomic regions that contain cancer-related immune response genes.
Sohrab Shah, Samuel Aparicio and colleagues analyze whole genomes and single cells from ovarian cancers in the peritoneal cavity to establish patterns of disease spread. They determine the clonal relationships between multiple tumor sites and characterize the migratory potential of genomically diverse clones.
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.
Multicellularity relies on molecular mechanisms that promote cooperation of individual cells and limit their inappropriate expansion. Here Chen et al. show that genes unique to multicellular organisms are preferentially inactivated during tumour evolution.
A recent study has demonstrated that serial profiling of resistance mutations in cell-free DNA (cfDNA) collected from the blood of patients with colorectal cancer can be used to track tumour evolution throughout the therapeutic course. This approach has the potential to inform personalized medicine by enabling dynamic adaptation of therapy.
Barrett’s oesophagus is thought to be a precursor lesion for oesophageal cancer, and predicting the benign lesions that progress to cancer is clinically important. Here, the authors use FISH to study the clonal evolution of Barrett’s oesophagus and show that genetic diversity and somatic mutations are present early in the benign disease.
Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer
Christine Iacobuzio-Donahue and colleagues report a detailed analysis of whole-genome sequencing data from primary and metastatic tumors in four patients with pancreatic cancer. They find that in each patient primary tumors and metastases have identical mutations in known driver genes.
Single-cell genome sequencing can provide detailed insights into the composition of single genomes that are not readily apparent when studying bulk cell populations. This Review discusses the considerable technical challenges of amplifying and interrogating genomes from single cells, emerging innovative solutions and various applications in microbiology and human disease, in particular in cancer.
Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma
Ming-Rong Wang, Benjamin Berman and colleagues perform whole-exome sequencing and global methylation profiling on different tumor regions of esophageal squamous cell carcinoma. They find evidence for intratumoral heterogeneity and identify late driver mutations targeting oncogenes and early driver mutations occurring in tumor-suppressor genes.
Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers
Luminal B oestrogen receptor positive breast cancers are generally aggressive tumors with poor outcomes. Here, the authors show that the kinase TLK2 is amplified and overexpressed in these tumors and correlates with reduced survival, TLK2 inhibition induces apoptosis in vitroand improves survival in mice.
Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish
Direct visualisation of heterogeneous cell populations in live animals has been challenging. Here, the authors optimize cell transplantation into optically clear immune-deficient zebrafish, and use intravital imaging to track and to assess functional diversity of individual cancer cells in vivo.
Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution
Papillary renal cell carcinoma (pRCC) is a subtype of kidney cancer characterized by highly variable clinical behaviour. Here the authors sequence either the genomes or exomes of 31 pRCCs and identify several genes in sub-clones and large copy number variants in major clones that may be important drivers of pRCC.
Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer
Castration-resistant prostate cancer frequently presents with persistent androgen receptor signalling. Here, the authors find that the androgen receptor is subject to genetic rearrangements, resulting in variants with ligand-independent activity.
Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis
Andrew Feinberg, Christine Iacobuzio-Donahue and colleagues describe the epigenomic reprogramming that occurs during pancreatic cancer progression. They also show that hematogenous metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP) and that oxPPP inhibition reverses chromatin reprogramming and blocks tumorigenic potential.
Phenotypic and genetic heterogeneity of cells within a tumour is thought to mediate treatment resistance and contribute to cancer progression. Here the authors show that genetic diversity in pediatric cancers is common after chemotherapy and can be quantified to predict survival.
Jaroslaw Maciejewski, Seishi Ogawa and colleagues examine the clonal dynamics of myelodysplastic syndromes (MDS) by analyzing whole-exome and targeted sequencing data from a large patient collection. They find that progression steps previously defined by pathologic criteria are accompanied by distinct molecular changes, and they show that driver genes can be classified into molecular subtypes differentially associated with low-risk MDS, high-risk MDS or secondary acute myeloid leukemia.
Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.
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.
Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution
Howard Chang, Ravindra Majeti and colleagues define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types and in acute myeloid leukemia cells. They identify potential regulators governing hematopoietic differentiation and genetic elements linked to regulatory evolution in cancer cells.
The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis
Helga Salvesen, Rameen Beroukhim, Scott Carter and colleagues study the evolutionary landscape of endometrial cancer by performing whole-exome sequencing of complex atypical hyperplasias, primary tumors and metastases. They identify recurrent alterations in primary tumors and suggest that driver events are generally shared by primary and metastatic tumors.
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These authors characterize circulating tumour cells from patients with advanced estrogen-receptor-positive/HER2-negative breast cancer and find that they can interconvert between two different states. One subpopulation acquires HER2 expression, displays activation of multiple RTK signalling pathways and is highly proliferative. A second population lacks HER2 expression but has elevated Notch1 levels. The HER2-negative population is less proliferative; it is highly resistant to cytotoxic agents but sensitive to Notch1 inhibitors. The rapid interconversion between proliferative and drug-resistant circulating tumour cell subpopulations raises the possibility that simultaneous combination therapy may be of clinical value.
An ex vivo model of human colon cancer enables study of the drivers of tumor development and invasion.
Raul Rabadan, Antonio Iavarone, Gaetano Finocchiaro, Do-Hyun Nam and colleagues analyze longitudinal genomic and transcriptomic data from 114 patients with glioblastoma. They find that relapse-associated clones typically exist before diagnosis, that expression subtypes are not stable under therapy and that recurrence tumors harbor specific alterations in several genes, including LTBP4 and MGMT.
Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition
Drug-tolerant but initially EGFRT790M-negative tumor cells that undergo genetic evolution to acquire resistance to EGFR inhibitors are more resistant than pre-existing EGFRT790M -positive clones to subsequent therapy.
This Review brings many aspects of pancreatic ductal adenocarcinoma research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for future study.
Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
Galanos and colleagues observe p21 accumulation in proliferating cancer cells, and show that in cultured p53-null cells, p21 can cause genomic instability by perturbing replication licensing through inhibition of the CRL4-CDT ubiquitin ligase.
Clonal evolution begins before the development of neoplasia in IBD, accelerated by repeated cycles of epithelial wounding and repair. Here, the authors summarize the biological drivers of mutant clone selection in IBD and discuss how an evolutionary perspective can improve cancer surveillance programmes and dysplasia management.
G&T-seq enables sequencing of DNA and mRNA from the same single cell, allowing the effects of genomic variation on transcription to be studied. It is compatible with any WGA method and so can be tailored to specific applications.
Cancer evolution is often depicted using a tree model and many current therapies target gene mutations mapped to the tree trunk. Here, Wei and Hsieh propose a novel paradigm—the river model—and examine how this model might describe phenotypically convergent events to better guide effective cancer control in renal cell carcinoma and overcome treatment-resistance that eventually develops in most patients.
Studying the genetic progression of many cancers is difficult as longitudinal samples are rarely available. Here, the authors analyse a patient with chronic lymphocytic leukaemia over a 29 year period and track the clonal evolution of the patient’s disease and response to therapy.
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.
Renal cell carcinoma (RCC) is a neoplasm of the renal epithelium and accounts for >90% of kidney cancers. Cancer genomic studies have identified numerous molecular events that lead to RCC and marked intra-tumour heterogeneity, which have prognostic and therapeutic relevance. In this Primer, the authors describe these advances, as well as highlight the considerable advances in the systemic treatment of metastatic RCC.
The routes and timing of metastatic dissemination during cancer progression remain shrouded in mystery. However, phylogenetic studies are beginning to shed new light on this process and various models have been proposed. In this Review, Kamila Naxerova and Rakesh Jain discuss the hypothesized trajectories of metastasis, and examine the extent to which the current phylogenetic evidence support these models. In addition, the experimental techniques of lineage tracing, their strengths and weaknesses, and future directions for studies using such methods are discussed.