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      Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

      1 , 2 , 20 , 1 , 20 , 1 , 20 , 1 , 20 , 1 , 20 , 3 , 20 , 4 , 20 , 5 , 20 , 2 , 20 , 6 , 1 , 2 , 2 , 7 , 5 , 8 , 9 , 1 , 10 , 10 , 10 , 2 , 5 , 11 , 11 , 1 , 2 , 10 , 12 , 13 , 13 , 2 , 2 , 1 , 1 , 7 , 3 , 14 , 14 , 15 , 16 , 17 , 17 , 18 , 18 , 18 , 17 , 18 , 17 , 18 , 1 , 7 , 19 , 21 , , PEACE, the TRACERx Renal Consortium


      Cell Press

      renal cell cancer, metastasis, evolution of metastasis, oligometastasis, solitary metastasis, cytoreductive nephrectomy, metastasectomy, chromosome instability, loss of 9p

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          Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

          Graphical Abstract


          • Evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases
          • Metastasis competence is afforded by chromosome complexity, but not driver mutation load
          • The hallmark genomic drivers of ccRCC metastasis are loss of 9p and 14q
          • Punctuated and branched evolution result in distinct patterns of metastases


          A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.

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          Most cited references 31

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          Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft

          Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumor progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis, and a xenograft derived from the primary tumor. The metastasis contained two de novo mutations and a large deletion not present in the primary tumor, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumor mutations, and displayed a mutation enrichment pattern that paralleled the metastasis (16 of 20 genes). Two overlapping large deletions, encompassing CTNNA1, were present in all three tumor samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared to the primary tumor suggest that secondary tumors may arise from a minority of cells within the primary.
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            Mechanisms governing metastatic dormancy and reactivation.

            Many cancer patients suffer from metastatic relapse several years after they have undergone radical surgery. Early cancer cell dissemination followed by a protracted period of dormancy potentially explains this prevalent clinical behavior. Increasing evidence suggests that the metastasis-initiating cells are cancer stem cells or revert to this functional state upon infiltrating a target organ. Their entry into dormancy and subsequent reactivation are governed by intrinsic programs and by contextual cues, which resemble those regulating the self-renewal capability of adult stem cells. In addition, metastatic cells undergoing reactivation are nursed by specialized extracellular matrix niches, which support positive signals, such as Wnt and Notch, and attenuate negative signals, such as BMP. In spite of significant remaining uncertainties, these findings provide a framework to understand the logic of metastatic dormancy and reactivation and open new avenues for therapeutic intervention. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Oligometastases revisited.

              We previously proposed a clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases. Here we review clinical and laboratory data that support the hypothesis that oligometastasis is a distinct clinical entity. Investigations of the prevalence, mechanism of occurrence, and position in the metastatic cascade, as well as the determination of molecular markers to distinguish oligometastatic from polymetastatic disease, are ongoing.

                Author and article information

                Cell Press
                19 April 2018
                19 April 2018
                : 173
                : 3
                : 581-594.e12
                [1 ]Translational Cancer Therapeutics Laboratory, the Francis Crick Institute, London NW1 1AT, UK
                [2 ]Renal and Skin Units, the Royal Marsden Hospital NHS Foundation Trust, London SW3 6JJ, UK
                [3 ]Department of Pathology, Cruces University Hospital, Biocruces Institute, University of the Basque Country, Barakaldo, Spain
                [4 ]Department of Urology, the Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK
                [5 ]Urology Centre, Guy’s & St Thomas’ NHS Foundation Trust, London, UK
                [6 ]Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK
                [7 ]Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK
                [8 ]Department of Cellular Pathology, Guy’s & St Thomas’ NHS Foundation Trust, London SE1 7EH, UK
                [9 ]Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
                [10 ]Department of Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
                [11 ]Experimental Histopathology Laboratory, the Francis Crick Institute, London NW1 1AT, UK
                [12 ]Department of Pathology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
                [13 ]Department of Pathology, University College London Hospitals, London WC1E 6DE, UK
                [14 ]Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
                [15 ]Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
                [16 ]Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO, USA
                [17 ]Roche Sequencing Solutions, Madison, Research & Development, Madison, WI, 53719, USA
                [18 ]Ventana Medical Systems, Tucson, AZ 85755, USA
                [19 ]Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK
                Author notes
                []Corresponding author charles.swanton@

                These authors contributed equally


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                © 2018 Francis Crick Institute

                This is an open access article under the CC BY-NC-ND license (



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