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Cancer Milestones

The ancient physician Hippocrates described the projection of blood vessels from a collection of cells as ‘karkinos’, the Greek word for crab. Today, we know this malignant growth as cancer. Although it remains one of our biggest killers, survival rates for several tumour types have improved dramatically in recent years. These Milestones celebrate two decades of breakthroughs in basic, translational and clinical research which have revolutionised our understanding and management of cancer.

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Milestones

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Computational analysis of over 9,000 cancer genomes, coupled with functional validation in cell lines, highlights combinations of mutations required for tumor progression. This integrated approach provides a framework to stratify patients on the basis of interdependent genetic aberrations.

Article | | Nature Genetics

Technological advances have enabled the analysis of whole genomes, leading to the identification of causal factors that present new opportunities to prevent cancer. The authors of this Review discuss relevant findings in cancer genetics and genomics from the perspective of global cancer prevention and present a conceptual framework for the translation of such findings into clinical practice and evidence-based policies.

Review Article | | Nature Reviews Clinical Oncology

This Perspective discusses how therapeutic resistance is not only driven by genetic evolution but often involves non-genetic adaptive mechanisms that are intimately linked. Acknowledging these adaptive processes will enable the development of innovative strategies to monitor and counteract non-genetic therapy resistance as well as provide novel therapeutic avenues.

Perspective | | Nature Reviews Cancer

Melanoma cells undergo less oxidative stress and less ferroptosis in lymph than in blood, owing to higher levels of oleic acid in lymph, and thus exposure to the lymphatic environment increases subsequent metastasis through blood.

Article | | Nature

Both genetic and non-genetic factors underlie the intratumoural heterogeneity that fuels cancer evolution. This Review discusses the application of single-cell multi-omics technologies to the study of cancer evolution, which capture and integrate the different layers of heritable information and reveal their complex interplay.

Review Article | | Nature Reviews Genetics

Large-scale datasets of increasing size and complexity are being produced in the microbiome and oncology field. This Perspective discusses the potential to harness gut microbiome analysis, big data and machine learning in cancer, and the potential and limitations with this approach.

Perspective | | Nature Reviews Gastroenterology & Hepatology

Preclinical evidence suggests that a fasting mimicking diet (FMD) can make cancer cells more vulnerable to chemotherapy, while protecting normal cells. In this randomized phase II clinical trial of 131 patients with HER2 negative early stage breast cancer, the authors demonstrate that FMD is safe and enhances the effects of neoadjuvant chemotherapy on radiological and pathological tumor response.

Article | Open Access | | Nature Communications

RAS proteins, which are frequently altered in cancer, were once considered undruggable, but compounds targeting some mutant RAS proteins have recently demonstrated clinical efficacy. In this Review, Malek and colleagues explore how these and other drugs that target RAS or associated pathways might be used effectively, particularly in combinations, and discuss other RAS-targeted therapies in the pipeline.

Review Article | | Nature Reviews Drug Discovery

Genomic profiling of renal cell carcinoma has demonstrated the clinical relevance of several genetic alterations in different disease subtypes. Pal and colleagues discuss the prognostic and predictive value of these alterations, and how they might help to improve treatment selection and patient outcomes.

Review Article | | Nature Reviews Nephrology

Further reading: Research and review articles

The onset of acquired resistance to treatment is virtually inevitable in patients with solid tumours. In this Review, the authors describe the role of tumour heterogeneity in the development of acquired resistance, potential treatment strategies that take into account the heterogeneity of patient's tumours, and how a better understanding of tumour heterogeneity might improve the outcomes of patients.

Review Article | | Nature Reviews Clinical Oncology

This Perspective discusses how therapeutic resistance is not only driven by genetic evolution but often involves non-genetic adaptive mechanisms that are intimately linked. Acknowledging these adaptive processes will enable the development of innovative strategies to monitor and counteract non-genetic therapy resistance as well as provide novel therapeutic avenues.

Perspective | | Nature Reviews Cancer

The platinum chemotherapeutics such as cisplatin and carboplatin are in clinical use in patients with BRCA2-mutated ovarian cancer. The initial response is generally good but most ovarian carcinomas ultimately become resistant to therapy. Two papers in this issue have identified a possible cause of this resistance as further mutation of the BRCA2 gene. Mutations in BRCA2 are associated with familial breast and ovarian cancer. Loss of BRCA2 function impairs DNA repair by homologous recombination and renders cells particular sensitive to cisplatin and also to PARP (poly (ADP-ribose) polymerase) inhibitors. The secondary 'resistance' mutations act by restoring the wild-type BRCA2 reading frame.

Letter | | Nature

Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers.

Letter | | Nature

Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers.

Letter | | Nature

Cytotoxic therapy can induce cellular senescence, a desirable outcome as it halts the uncontrolled proliferation of cancer cells. Less desirable is the build-up of senescent cells. Working with a mouse lymphoma model, Clemens Schmitt and colleagues show that an increased dependence on metabolic processes makes chemotherapy-induced senescent cells selectively vulnerable to drugs that block glucose utilization or autophagy. Both genetic and pharmacological blockade of glucose metabolism prompt tumour regression and improve survival in the mouse model, suggesting that targeted combination therapies may be of value in patients with lymphomas and possibly other cancers in which cancer cells undergo chemotherapy-induced senescence.

Letter | | Nature

Various tissues and organs accumulate senescent cells during normal ageing, but it is not known whether — or how — these cells influence health and lifespan. Jan van Deursen and colleagues show that when senescent cells accumulate during adulthood they are a negative influence on lifespan and promote age-dependent changes in multiple organs. Clearance of these cells delayed tumorigenesis and attenuated age-related deterioration of several organs without overt side effects. This finding suggests that therapeutic removal of senescent cells may be able to extend healthy lifespan.

Article | | Nature

There is laboratory evidence from in vitro and animal studies to suggest that antioxidants may suppress the development of cancer, though there is little conclusive evidence as to their effect in clinical conditions. Nevertheless it comes as something of a surprise to find that in certain conditions antioxidants can help promote cancer cell survival and proliferation. Normal epithelial cells die if they become detached from the structurally supportive extracellular matrix, but in breast cancer, cancer-causing genes such as ERBB2 can provide survival signals to detached tumorigenic cells. Schafer et al. show that cell detachment also causes metabolic defects that can be rescued both by ERBB2 and by antioxidants, which appear to act by boosting cellular energy levels via fatty acid oxidation. The findings point to novel mechanisms that could be exploited by cancer cells to enhance their survival in altered matrix environments.

Letter | | Nature

An in vivo RNAi screen of metabolic enzymes and transporters is used to identify, among other genes, phosphoglycerate dehydrogenase (PHGDH) as a gene required for breast tumour growth. PHGDH resides in a region of chromosome 1p that is often amplified in breast cancers, leading to PHGDH overexpression. Elevated levels of PHGDH cause increased metabolic flux through the serine synthesis pathway, which in turn contributes significantly to the flux of glutamine to α-ketoglutarate through the tricarboxylic acid cycle. These observations suggest that targeting PHGDH or the serine biosynthesis pathway in general might be of therapeutic value in the subset of breast cancers with high PHGDH expression.

Letter | | Nature

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

Letter | | Nature Genetics

Next-generation sequencing approaches have been used to investigate the genomes and transcriptomes of an oestrogen-receptor-α-positive metastatic lobular breast cancer from a patient — rather than from a cell line or xenograft — over a 9-year period between the diagnosis of the primary tumour and the appearance of metastasis. Comparison of the somatic non-synonymous coding mutations in the metastasis and the primary tumour of the same patient and the combined analysis of genome and transcriptome data provided insights into the mutational evolution that can occur with disease progression. The cover shows sequence elements of the HAUS3 locus, one of the genes found to be mutated in the tissue (shown in the background) from the primary lobular cancer used for this work.

Letter | Open Access | | Nature

The two cancer genome sequences presented in this issue demonstrate how next-generation sequencing technologies can inform us about mutational processes, repair pathways and gene networks associated with cancer development. First, the genome of a cell line derived from a bone marrow metastasis in a patient who had small-cell lung cancer. This cancer is typical of the type induced by smoking, and the sequence contains mutation signatures characteristic of some of the more than 60 carcinogens present in tobacco smoke. The second paper compares the whole genome sequence of a melanoma cell line to a lymphoblastoid cell line from the same individual. This, the first complete mutational analysis of a solid tumour, reveals a dominant mutational signature reflecting DNA damage due to exposure to ultraviolet light.

Article | Open Access | | Nature

The two cancer genome sequences presented in this issue demonstrate how next-generation sequencing technologies can inform us about mutational processes, repair pathways and gene networks associated with cancer development. First, the genome of a cell line derived from a bone marrow metastasis in a patient who had small-cell lung cancer. This cancer is typical of the type induced by smoking, and the sequence contains mutation signatures characteristic of some of the more than 60 carcinogens present in tobacco smoke. The second paper compares the whole genome sequence of a melanoma cell line to a lymphoblastoid cell line from the same individual. This, the first complete mutational analysis of a solid tumour, reveals a dominant mutational signature reflecting DNA damage due to exposure to ultraviolet light.

Article | Open Access | | Nature

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Article | Open Access | | Nature

Most cancer genes are mutated at intermediate frequencies, appearing in less than one in five samples of a particular tumour type, so the accurate identification of cancer genes needs to be based on large-scale sampling in order to take account of this mutation-rate heterogeneity. This study presents a statistical analysis of 21 tumour types from more than 4,700 tumour–normal pairs. The authors identify 33 previously unknown genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Further analyses suggest that near-saturation may be achieved with between 600 and 5,000 samples for a given tumour type, depending on background mutation rate.

Article | | Nature

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Article | Open Access | | Nature

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

Article | | Nature Medicine

Although mutant H3K27M histones inhibit PRC2 in diffuse intrinsic pontine gliomas, these tumors exhibit significant amounts of PRC2 activity. The repression of several genes, including INK4A, by residual EZH2 activity is required for tumor growth, and EZH2 inhibitors therefore represent potential therapies for these patients.

Article | | Nature Medicine

Recent studies have identified a number of oncogenic histone point mutations in different cancers. Here the authors provide evidence that H3.3 G34R substitution mutation, which is found in paediatric gliomas, causes changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases.

Article | Open Access | | Nature Communications

With the latest DNA sequencing technologies it is now possible to screen an entire genome for the genetic changes associated with tumour progression. This approach has been used to obtain complete sequences of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer: the primary tumour, peripheral blood, a brain metastasis and a first-passage xenograft derived from the primary tumour. Mutational analysis suggests that the metastasis tumour specifically selects a subset of cells from the primary tumour that contain pre-existing mutations, and also develops a small number of de novo mutations.

Article | | Nature

Genome-wide analysis of cancer cells in individual patients has revealed extensive genetic heterogeneity. Two groups have now mapped genetic homogeneity in patients with acute lymphoblastic leukaemia (ALL). Mel Greaves and colleagues obtained mutational profiles of large numbers of single cells from 60 individuals with ETV6RUNX1-positive ALL, while John Dick and colleagues profile BCR-ABL1-positive ALL. Both groups deduce the evolutionary path by which different subclones emerge during disease progression. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insight into the heterogeneity of these functional subpopulations at the genetic level. This work has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells.

Article | | Nature

Tumours are known to be genetically heterogeneous, but it is proving difficult to dissect this heterogeneity at the single-cell level. A combination of whole-genome amplification and sequencing of single nuclei separated by fluorescence activated cell sorting now reveals the population structure of breast tumours from two patients. In both, tumour growth is by punctuated clonal expansions with few persistent intermediates, in contrast to the many gradual models of tumour progression. Single-cell sequencing of this type — once it becomes cheaper — is likely to have clinical implications for cancer prognosis and staging.

Letter | | Nature

Genome-wide analysis of cancer cells in individual patients has revealed extensive genetic heterogeneity. Two groups have now mapped genetic homogeneity in patients with acute lymphoblastic leukaemia (ALL). Mel Greaves and colleagues obtained mutational profiles of large numbers of single cells from 60 individuals with ETV6RUNX1-positive ALL, while John Dick and colleagues profile BCR-ABL1-positive ALL. Both groups deduce the evolutionary path by which different subclones emerge during disease progression. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insight into the heterogeneity of these functional subpopulations at the genetic level. This work has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells.

Article | | Nature

Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.

Article | Open Access | | Nature Communications

Treatment of KRASG12C-mutant cancer cells with the KRAS(G12C) inhibitor AMG 510 leads to durable response in mice, and anti-tumour activity in patients suggests that AMG 510 could be effective in patients for whom treatments are currently lacking.

Article | | Nature

The human microbiota influences a whole range of physiological functions. In this Review, Roy and Trinchieri discuss our current understanding of how the gut microbiota modulates responses to cancer therapy as well as mediating susceptibility to toxic side effects.

Review Article | | Nature Reviews Cancer

In this Viewpoint article, we asked four scientists working on the cancer microbiome to provide their opinions on the current state of the field, where the research is heading and the challenges of implementing this field for clinical utility.

Viewpoint | | Nature Reviews Cancer