Publications by authors named "Peter Van Loo"

112 Publications

A pan-cancer landscape of somatic mutations in non-unique regions of the human genome.

Nat Biotechnol 2021 Jul 19. Epub 2021 Jul 19.

The Francis Crick Institute, London, UK.

A substantial fraction of the human genome displays high sequence similarity with at least one other genomic sequence, posing a challenge for the identification of somatic mutations from short-read sequencing data. Here we annotate genomic variants in 2,658 cancers from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort with links to similar sites across the human genome. We train a machine learning model to use signals distributed over multiple genomic sites to call somatic events in non-unique regions and validate the data against linked-read sequencing in an independent dataset. Using this approach, we uncover previously hidden mutations in ~1,700 coding sequences and in thousands of regulatory elements, including in known cancer genes, immunoglobulins and highly mutated gene families. Mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation burden and substitution profiles. The analysis provides a systematic summary of the mutation events in non-unique regions at a genome-wide scale across multiple human cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-021-00971-yDOI Listing
July 2021

E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion.

Oncogene 2021 Sep 18;40(37):5567-5578. Epub 2021 Jun 18.

Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK.

The ubiquitin-proteasome system maintains protein homoeostasis, underpins the cell cycle, and is dysregulated in cancer. However, the role of individual E3 ubiquitin ligases, which mediate the final step in ubiquitin-mediated proteolysis, remains incompletely understood. Identified through screening for cancer-specific endogenous retroviral transcripts, we show that the little-studied E3 ubiquitin ligase HECTD2 exerts dominant control of tumour progression in melanoma. HECTD2 cell autonomously drives the proliferation of human and murine melanoma cells by accelerating the cell cycle. HECTD2 additionally regulates cancer cell production of immune mediators, initiating multiple immune suppressive pathways, which include the cyclooxygenase 2 (COX2) pathway. Accordingly, higher HECTD2 expression is associated with weaker anti-tumour immunity and unfavourable outcome of PD-1 blockade in human melanoma and counteracts immunity against a model tumour antigen in murine melanoma. This central, multifaceted role of HECTD2 in cancer cell-autonomous proliferation and in immune evasion may provide a single target for a multipronged therapy of melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-021-01885-4DOI Listing
September 2021

An integrative analysis of the age-associated multi-omic landscape across cancers.

Nat Commun 2021 04 20;12(1):2345. Epub 2021 Apr 20.

Integrative Genomics of Ageing Group, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

Age is the most important risk factor for cancer, as cancer incidence and mortality increase with age. However, how molecular alterations in tumours differ among patients of different age remains largely unexplored. Here, using data from The Cancer Genome Atlas, we comprehensively characterise genomic, transcriptomic and epigenetic alterations in relation to patients' age across cancer types. We show that tumours from older patients present an overall increase in genomic instability, somatic copy-number alterations (SCNAs) and somatic mutations. Age-associated SCNAs and mutations are identified in several cancer-driver genes across different cancer types. The largest age-related genomic differences are found in gliomas and endometrial cancer. We identify age-related global transcriptomic changes and demonstrate that these genes are in part regulated by age-associated DNA methylation changes. This study provides a comprehensive, multi-omics view of age-associated alterations in cancer and underscores age as an important factor to consider in cancer research and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22560-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058097PMC
April 2021

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Cell 2021 Apr 7;184(8):2239-2254.e39. Epub 2021 Apr 7.

Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054914PMC
April 2021

Promises and challenges of adoptive T-cell therapies for solid tumours.

Br J Cancer 2021 May 29;124(11):1759-1776. Epub 2021 Mar 29.

Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144577PMC
May 2021

Breast tumours maintain a reservoir of subclonal diversity during expansion.

Nature 2021 04 24;592(7853):302-308. Epub 2021 Mar 24.

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03357-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049101PMC
April 2021

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.

Cell 2021 02 27;184(3):596-614.e14. Epub 2021 Jan 27.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address:

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933824PMC
February 2021

A practical guide to cancer subclonal reconstruction from DNA sequencing.

Nat Methods 2021 02 4;18(2):144-155. Epub 2021 Jan 4.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Subclonal reconstruction from bulk tumor DNA sequencing has become a pillar of cancer evolution studies, providing insight into the clonality and relative ordering of mutations and mutational processes. We provide an outline of the complex computational approaches used for subclonal reconstruction from single and multiple tumor samples. We identify the underlying assumptions and uncertainties in each step and suggest best practices for analysis and quality assessment. This guide provides a pragmatic resource for the growing user community of subclonal reconstruction methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41592-020-01013-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867630PMC
February 2021

Pervasive chromosomal instability and karyotype order in tumour evolution.

Nature 2020 11 2;587(7832):126-132. Epub 2020 Sep 2.

Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2 breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2698-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611706PMC
November 2020

Drivers underpinning the malignant transformation of giant cell tumour of bone.

J Pathol 2020 12 6;252(4):433-440. Epub 2020 Oct 6.

Department of Pathology (research), University College London Cancer Institute, London, UK.

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432151PMC
December 2020

Ethanol exposure increases mutation rate through error-prone polymerases.

Nat Commun 2020 07 21;11(1):3664. Epub 2020 Jul 21.

Laboratory of Systems Biology, VIB-KU Leuven Center for Microbiology, Leuven, Belgium.

Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also provide a route to better understand and prevent ethanol-associated carcinogenesis in higher eukaryotes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17447-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374746PMC
July 2020

Allele-specific multi-sample copy number segmentation in ASCAT.

Bioinformatics 2021 07;37(13):1909-1911

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.

Motivation: Allele-specific copy number alterations are commonly used to trace the evolution of tumours. A key step of the analysis is to segment genomic data into regions of constant copy number. For precise phylogenetic inference, breakpoints shared between samples need to be aligned to each other.

Results: Here, we present asmultipcf, an algorithm for allele-specific segmentation of multiple samples that infers private and shared segment boundaries of phylogenetically related samples. The output of this algorithm can directly be used for allele-specific copy number calling using ASCAT.

Availability And Implementation: asmultipcf is available as part of the ASCAT R package (version ≥2.5) from github.com/Crick-CancerGenomics/ascat/.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btaa538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317109PMC
July 2021

DNA copy number motifs are strong and independent predictors of survival in breast cancer.

Commun Biol 2020 04 2;3(1):153. Epub 2020 Apr 2.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70 N-0310, Oslo, Norway.

Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-0884-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118095PMC
April 2020

Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution.

Nat Genet 2020 03 5;52(3):283-293. Epub 2020 Mar 5.

Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.

Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-0584-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116784PMC
March 2020

The evolutionary history of 2,658 cancers.

Nature 2020 02 6;578(7793):122-128. Epub 2020 Feb 6.

University of Toronto, Toronto, Ontario, Canada.

Cancer develops through a process of somatic evolution. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1907-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054212PMC
February 2020

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Nat Genet 2020 03 5;52(3):306-319. Epub 2020 Feb 5.

Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0562-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058536PMC
March 2020

A community effort to create standards for evaluating tumor subclonal reconstruction.

Nat Biotechnol 2020 01 9;38(1):97-107. Epub 2020 Jan 9.

Big Data Institute, University of Oxford, Oxford, UK.

Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking. To address this need, we systematically assess methods for reconstructing tumor subclonality. First, we elucidate the main algorithmic problems in subclonal reconstruction and develop quantitative metrics for evaluating them. Then we simulate realistic tumor genomes that harbor all known clonal and subclonal mutation types and processes. Finally, we benchmark 580 tumor reconstructions, varying tumor read depth, tumor type and somatic variant detection. Our analysis provides a baseline for the establishment of gold-standard methods to analyze tumor heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-019-0364-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956735PMC
January 2020

Translating insights into tumor evolution to clinical practice: promises and challenges.

Genome Med 2019 03 29;11(1):20. Epub 2019 Mar 29.

The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination. Circulating tumor DNA and circulating tumor cells can be leveraged for monitoring the efficacy of therapy and for tracking the emergence of resistant subclones. The evolutionary history of tumors can be deduced for late-stage cancers, either directly by sampling precursor lesions or by leveraging computational approaches to infer the timing of driver events. This approach can identify recurrent early driver mutations that represent promising avenues for future early detection strategies. Emerging evidence suggests that mutational processes and complex clonal dynamics are active even in normal development and aging. This will make discriminating developing malignant neoplasms from normal aging cell lineages a challenge. Furthermore, insight into signatures of mutational processes that are active early in tumor evolution may allow the development of cancer-prevention approaches. Research and clinical studies that incorporate an appreciation of the complex evolutionary patterns in tumors will not only produce more meaningful genomic data, but also better exploit the vulnerabilities of cancer, resulting in improved treatment outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-019-0632-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440005PMC
March 2019

Neoantigen-directed immune escape in lung cancer evolution.

Nature 2019 03 20;567(7749):479-485. Epub 2019 Mar 20.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK.

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1032-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954100PMC
March 2019

Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways.

Cancer Cell 2019 03;35(3):441-456.e8

Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK. Electronic address:

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428691PMC
March 2019

Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.

Nat Commun 2019 01 28;10(1):525. Epub 2019 Jan 28.

The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.

The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'K.P.W. is President of Tempus Lab, Inc., Chicago, IL, USA'. This has now been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-08512-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349916PMC
January 2019

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Nature 2019 02;566(7742):E1

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-0883-2DOI Listing
February 2019

Author Correction: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Nat Commun 2019 01 14;10(1):288. Epub 2019 Jan 14.

Department of Surgery, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07886-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331546PMC
January 2019

Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.

Nat Commun 2018 12 17;9(1):5397. Epub 2018 Dec 17.

The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc., Chicago, IL, USA was inadvertently omitted.This has now been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297227PMC
December 2018

Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations.

Genome Med 2018 11 29;10(1):92. Epub 2018 Nov 29.

Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Postboks 4953 Nydalen, 0424, Oslo, Norway.

Background: Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels.

Methods: A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods.

Results: In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime.

Conclusions: Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy.

Trial Registration: NCT00773695 . Registered 15 October 2008.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-018-0601-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262977PMC
November 2018

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Nat Commun 2018 10 16;9(1):4181. Epub 2018 Oct 16.

Department of Surgery, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06616-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191428PMC
October 2018

Timing somatic events in the evolution of cancer.

Genome Biol 2018 07 24;19(1):95. Epub 2018 Jul 24.

The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

Cancer arises through the accumulation of somatic mutations over time. An understanding of the sequence of events during this process should allow both earlier diagnosis and better prediction of cancer progression. However, the pathways of tumor evolution have not yet been comprehensively characterized. With the advent of whole genome sequencing, it is now possible to infer the evolutionary history of single tumors from the snapshot of their genome taken at diagnosis, giving new insights into the biology of tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-018-1476-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057033PMC
July 2018

Association between crural vessel patency and successful transmetatarsal amputation: a single centre experience.

S Afr J Surg 2018 Jun;56(2):50-53

Department of General and Vascular Surgery, James Cook University Hospital, Middlesbrough, United Kingdom.

Background: Transmetatarsal amputation (TMA) has a reputation for failure, centred around wound breakdown. No study has looked at the direct association between the patency of individual crural arteries and the healing of TMA. TMA relies on a posterior skin flap which derives its blood supply from the posterior tibial (PT) artery. We investigated the association between PT patency and achievement of successful TMA.

Methods: A retrospective review of all patients undergoing TMA for complications of peripheral arterial occlusive disease in a regional vascular tertiary referral centre over a 9 year period (2006-2015). TMA was considered successful by the absence of a higher-level amputation. Follow-up was for a minimum of 12 months.

Results: 24 patients (21 male; mean age 64 years) were studied. TMA was successful in 16 (67%). On statistical analysis, successful TMA was not significantly associated with vessel patency in either superficial femoral artery (SFA), or any single or combination of named crural artery.

Conclusion: TMA healing can be achieved in the absence of a patent posterior tibial artery. We support the role of TMA in selected patients, given its benefits compared to transtibial amputation.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2018
-->