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Key Points The functional classification system introduced here divides the genes that shape the cancer epigenome into three categories: epigenetic modifiers that directly modify the cancer epigenome and are frequent targets of mutations and epimutations; epigenetic mediators that drive the tumour or its progenitor cells towards a more stem-like state; and epigenetic modulators that transmit environmental signals to epigenetic modifiers. Epigenetic mediator-induced epigenetic variation in the cells of origin might lead to increased phenotypic flexibility and heterogeneity long before the emergence of oncogenic mutations and is subsequently selected in the tumour tissue during progression. Sites of increased epigenetic variation in precancerous lesions and cancer localize to large domains, called hypomethylated blocks, that overlap with regions of repressive chromatin modifications acquired during development (large organized chromatin K9 modifications) and are particularly sensitive to ageing and cancer-predisposing environmental signals. Increased epigenetic variation is a predictor of cancer risk and cancer progression; it promotes the adaptation of the tumour tissue to changing environmental cues by continuously re-establishing tumour cell phenotypic heterogeneity. The mechanism of increased epigenetic variation is functionally intertwined with the perturbations of the 3D genome organization and the disruption of heterochromatin compartments within the nuclear architecture. 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 year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

Lung cancer is the most common cause of cancer-related deaths globally. Although smoking-related lung cancers continue to account for the majority of diagnoses, smoking rates have been decreasing for several decades. Lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths worldwide in 2023, preferentially occurring in women and Asian populations. As smoking rates continue to decline, understanding the aetiology and features of this disease, which necessitate unique diagnostic and treatment paradigms, will be imperative. New data have provided important insights into the molecular and genomic characteristics of LCINS, which are distinct from those of smoking-associated lung cancers and directly affect treatment decisions and outcomes. Herein, we review the emerging data regarding the aetiology and features of LCINS, particularly the genetic and environmental underpinnings of this disease as well as their implications for treatment. In addition, we outline the unique diagnostic and therapeutic paradigms of LCINS and discuss future directions in identifying individuals at high risk of this disease for potential screening efforts.Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

While the processing of mRNA is essential for gene expression, recent findings have highlighted that RNA processing is systematically altered in cancer. Mutations in RNA splicing factor genes and the shortening of 3′ untranslated regions are widely observed. Moreover, evidence is accumulating that other types of RNAs, including circular RNAs, can contribute to tumorigenesis. In this Review, we highlight how altered processing or activity of coding and non-coding RNAs contributes to cancer. We introduce the regulation of gene expression by coding and non-coding RNA and discuss both established roles (microRNAs and long non-coding RNAs) and emerging roles (selective mRNA processing and circular RNAs) for RNAs, highlighting the potential mechanisms by which these RNA subtypes contribute to cancer. The widespread alteration of coding and non-coding RNA demonstrates that altered RNA biogenesis contributes to multiple hallmarks of cancer.This Review discusses how altered processing or activity of coding and non-coding RNAs contributes to cancer, introducing the regulation of gene expression by coding and non-coding RNA and discussing both established and emerging roles for RNAs in cancer.

The natural history of cancers can be understood through the lens of evolution given that the driving forces of cancer development are mutation and selection of fitter clones. Cancer growth and progression are spatial processes that involve the breakdown of normal tissue organization, invasion and metastasis. For these reasons, spatial patterns are an integral part of histological tumour grading and staging as they measure the progression from normal to malignant disease. Furthermore, tumour cells are part of an ecosystem of tumour cells and their surrounding tumour microenvironment. A range of new spatial genomic, transcriptomic and proteomic technologies offers new avenues for the study of cancer evolution with great molecular and spatial detail. These methods enable precise characterizations of the tumour microenvironment, cellular interactions therein and micro-anatomical structures. In conjunction with spatial genomics, it emerges that tumours and microenvironments co-evolve, which helps explain observable patterns of heterogeneity and offers new routes for therapeutic interventions.In this Review, the authors discuss our latest understanding of the spatial aspects of cancer evolution, including the roles of cancer subclonal structure, tissue architecture, and interactions between cancer cells and diverse cell types of the microenvironment at local and distant sites.

RNA methylation is an important epigenetic modification. Recent studies on RNA methylation mainly focus on the m6A modification of mRNA, but very little is known about the m5C modification. NSUN2 is an RNA methyltransferase responsible for the m5C modification of multiple RNAs. In this study, we knocked down the NSUN2 gene in HepG2 cells by CRISPR/Cas9 technology and performed high-throughput RNA-BisSeq. An important tumor-related lncRNA H19 was identified to be targeted by NSUN2. Studies have shown that the expression of H19 lncRNA is abnormally elevated and has a carcinogenic effect in many types of tumors. Our results demonstrated that m5C modification of H19 lncRNA can increase its stability. Interestingly, m5C-modified H19 lncRNA can be specifically bound by G3BP1, a well-known oncoprotein which further leads to MYC accumulation. This may be a novel mechanism by which lncRNA H19 exerts its oncogenic effect. Besides, both the m5C methylation level and the expression level of H19 lncRNA in hepatocellular carcinoma tissues were significantly higher than those in adjacent non-cancer tissues, which were closely associated with poor differentiation of hepatocellular carcinoma (HCC). In conclusion, we found that H19 RNA is a specific target for the NSUN2 modifier. The m5C-modified H19 lncRNA may promote the occurrence and development of tumors by recruiting the G3BP1 oncoprotein. Our findings may provide a potential target and biomarker for the diagnosis and treatment of HCC.

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance. In their Review article, Fuchs and colleagues discuss how a single or a few mutations in adult cells can lead to invasive cancers without a high mutational burden, demonstrating that non-genetic factors induce the epigenetic changes necessary for tumorigenesis.

Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized.

Prime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor DNA as a template. PEs facilitate nucleotide substitutions or local insertions or deletions within the genome based on the template sequence encoded within the prime editing guide RNA (pegRNA). However, the efficacy of prime editing in adult mice has not been established. Here we report an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines. Using this genome modification system, we could also seed tumor formation through somatic cell editing in the adult mouse. Finally, we successfully utilize dual adeno-associated virus (AAVs) for the delivery of a split-intein prime editor and demonstrate that this system enables the correction of a pathogenic mutation in the mouse liver. Our findings further establish the broad potential of this genome editing technology for the directed installation of sequence modifications in vivo, with important implications for disease modeling and correction. Prime editors use a template sequence within their pegRNA to facilitate nucleotide substitutions or local indels. Here the authors use AAVs to deliver a split-intein prime editor in vivo to correct a pathogenic mutation.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 , 2 , 3 , 4 – 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications. Exome sequence data from 628,388 individuals was used to identify 24 risk loci in 40,208 carriers of clonal haematopoiesis of indeterminate potential and link them to other conditions including COVID-19, cardiovascular disease and cancer.

Key Points The architecture of inherited genetic susceptibility to cancer is defined by a spectrum of predisposition alleles that have differing frequencies and impact. Genome-wide association studies (GWAS) provide an agnostic approach to the identification of genetic variation influencing cancer risk. For most cancers, GWAS have been performed, and hundreds of risk alleles have been identified, most of which are common and individually confer a modest increase in risk. Most cancer risk loci identified through GWAS locate to non-coding regions of the genome and influence gene expression through diverse mechanisms. As well as improving our understanding of cancer, information from GWAS has direct clinical relevance in identifying nongenetic aetiological risk factors, optimising population screening, identifying therapeutic targets, drug repositioning and prognostication. Although challenging, deciphering the biological basis of identified associations is necessary to fully realise the potential of GWAS. Genome-wide association studies (GWAS) uncover the impact of genetic variation on the risk of many common cancers. This Review discusses current insights and how understanding the biological basis of these associations is required to maximise the clinical benefit of GWAS. Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS.