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Charles Swanton obtained a PhD from the Imperial Cancer Research Fund Laboratories (now the Francis Crick Institute) in 1998 and completed his medical oncology and Cancer Research UK (CRUK)-funded postdoctoral clinical scientist training in 2008. He was appointed chair in personalized cancer medicine at the UCL Cancer Institute, and consultant thoracic medical oncologist at UCL Hospitals in 2011. In 2016, he was awarded a Napier Professor in Cancer by the Royal Society, and in 2017 he was appointed principal group leader of the Francis Crick Institute. He is co-director of the Cancer Research UK Lung Cancer Centre of Excellence, and chief clinician of Cancer Research UK.

Charles Swanton and colleagues used multiregion exome sequencing to study the evolutionary histories of ten clear cell renal cell carcinomas. They observed marked intratumoral heterogeneity in all cases, with extensive evidence of parallel evolution of tumor subclones and only a small number of truncal driver events.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Few clinical trials incorporate studies of evolutionary cancer biology, despite the frequent emergence of acquired resistance to anticancer therapies. This problem motivated the first CRUK Marshall Symposium on Cancer Evolution in May 2017, which provided a forum for evolutionary and ecological theorists, cancer biologists, and clinicians to consider how evolutionary biology might inform improvements in cancer medicine. Herein, we discuss the key themes and opportunities for the future.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

The first long-term study of how lung cancer evolves is revealing that therapies targeting multiple proteins in tumour cells could help to outpace the disease.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma. Here we show that identification of clonal somatic copy number alterations in frequently amplified cancer genes could inform therapeutics for precision medicine.

CONIPHER is a computational framework for accurately inferring subclonal structure and the phylogenetic tree from multisample tumor sequencing, accounting for both copy number alterations and mutation errors.

The transcripts generated by frameshifts and indels in cancer are frequently degraded by nonsense mediated decay. Here, the authors show that some of these transcripts can escape this degradation mechanism and their prevalence correlates with tumour response to immunotherapy.

Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

Analysis of whole-genome doubling (WGD) by using cancer sequencing data combined with simulations of tumor evolution suggests that there is negative selection against homozygous loss of essential genes before WGD but not after.

DNA mismatch repair deficiency (MMRd) is associated with elevated tumor mutational burden (TMB) and exceptional immunotherapy responses, yet some patients experience no clinical benefit. Recent work proposes that high intra-tumoral heterogeneity can offset immunogenicity in sporadic MMRd, suggesting a potential mechanism of immunotherapy failure.

Inactivation of tumor suppressor genes such asSETD2, KDM6A, KDM5C and PBRM1 has been reported in renal cell carcinoma (RCC)—notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Here, Larkin et al. discuss the role of histone and chromatin regulation in RCC biology and how understanding of epigenetic mechanisms might identify novel therapeutic targets in RCC.

The spatial and physical nature of tumour growth remains unclear. Combining whole-tumour images from clear cell renal cell carcinoma with genomic data, the authors show more aggressive subclonal growth and metastasizing subclones in the tumour centre.

TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.

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.

In this Perspectives article, the authors propose that lower histological grade in breast cancer might be a hallmark of relative chromosomal stability, which in turn might be predictive of additional benefit from taxane-based chemotherapy in women with oestrogen-receptor-positive cancer. They interpret published data to on the relationships between tumour grade, chromosomal instability and intratumour heterogeneity and discuss the potential use of chromosomal instability to tailor therapy.

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.

Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions

Analysis of a large cohort of EGFR-mutant lung cancer cell-free DNA samples along with longitudinal samples from a patient with EGFR-mutant lung cancer identifies pathways that inhibit EGFR-inhibitor response. Co-occurring genetic alterations influence clinical outcomes and underscore the need for combination therapies.

Activated PI3K causes cancer, but the role of active PI3K mutations in early stages of malignancy are unclear. Here, the authors show in a mouse model that active PI3K induces centrosome amplification via AKT, ROCK, CDK2/Cyclin E and nucleophosmin, and increased tolerance of genome doubling.

Pulmonary venous tumor cells disseminating before tumor resection are heterogeneous, predict relapse and seed future metastasis of lung cancer

We reflect on the past 10 months of clinical activity in oncology in the UK during the COVID-19 pandemic and suggest how services can be protected during subsequent waves of infection.

Intratumoral genetic heterogeneity of driver somatic mutations is present in a variety of tumor types, yet the extent of heterogeneity is variable. We propose that this variation is a reflection of the inherent biology of a given tumor type, representing the pace of metastatic dissemination and hence clinical disease course.

By integrating discovery science with clinical practice and therapeutic intervention, clinician-scientists fulfil a unique role in cancer research. However, their numbers are in decline, which is creating the need for flexible training and research opportunities to ensure their future.

Intratumour heterogeneity is a critical driver of cancer progression and treatment failure. TRACERx Renal is a prospective study that aims to define the evolutionary trajectories of renal cancer in space and time through multiregion and longitudinal tumour sampling.

Tumour evolution, which results in the existence of multiple distinct populations of cancer cells within the same tumour and the same patient, is increasingly appreciated to have a key role in drug resistance. In this article, we discuss the implications for drug development, including approaches to reduce the likelihood of the emergence of drug resistance.

Ghorani et al. use a multiomics approach to characterize the effect of tumour mutational burden on the differentiation of CD4 and CD8 T cell subpopulations in non-small cell lung cancer.

A mechanism to explain chromosomal instability (CIN) in colorectal cancer is demonstrated; three new CIN-suppressor genes (PIGN, MEX3C and ZNF516) encoded on chromosome 18q are identified, the loss of which leads to DNA replication stress, resulting in structural and numerical chromosome segregation errors, which are shown to be identical to phenotypes seen in CIN cells.

Glioblastoma, the most common form of brain cancer in adults, has a dismal prognosis and has proven recalcitrant to novel targeted therapies and immunotherapies. Extrachromosomal DNAs (ecDNAs) harbouring oncogenes are increasingly recognized as important drivers of tumour development, evolution and resistance to treatment, particularly in patients with glioblastoma. In this Perspective, the authors summarize key reasons for the failed clinical translation of new therapies for glioblastoma, highlighting the important contributions of ecDNAs. They then focus on the opportunities and challenges of utilizing ecDNAs to improve the likelihood of success in the development of precision medicines for this disease.

Liquid biopsy approaches hold great promise in early cancer diagnosis or minimal residual disease monitoring for cancer recurrence. Herein, the authors evaluate contemporary next-generation sequencing approaches to circulating tumour DNA detection in these contexts, with a focus on studies in patients with non-small-cell lung cancer. They discuss the feasibility of introducing these strategies into the clinic, highlighting the technical and analytical challenges, as well as possible solutions.

Based on a consensus conference of experts in the evolution and ecology of cancer, this article proposes a framework for classifying tumours that includes four evolutionary and ecological processes: neoplastic cell diversity and changes over time in that diversity, hazards to cell survival and available resources.

New technologies have led to an explosive increase in the number of biomarkers thought to be associated with prognosis and treatment outcome in colorectal cancer. How effective are the biomarkers already in the public domain?

Recent next-generation sequencing studies have captured the spatial and temporal evolutionary patterns that shape cancer. This Review provides an overview of the theoretical models of tumour evolution and discusses what to consider when inferring evolutionary dynamics from genomic data.