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Intratumor heterogeneity reflects clinical disease course

Nature Cancer volume 1, pages 3–6 (2020)Cite this article

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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.

Work over the past decade has revealed wide variation in cancer subclonal structures across tumor types, with key insights emerging as to how ITH may manifest. Broadly speaking, these evolutionary phenomena illustrate that tumors at one end of the spectrum follow a clear Darwinian growth pattern, displaying extensive ITH characterized by branched heterogeneous somatic mutations and selection of subclonal driver mutations and DNA copy-number events6 (Fig. 1b). At the other end of the spectrum are tumors characterized by a monoclonal growth pattern that display limited ITH for somatic mutations and have multiple clonal (truncal) driver events, and alterations in both somatic coding regions and copy number. In such tumors, these characteristics are all present in the most recent common ancestor (MRCA), and subsequent evolutionary trajectories seem to be genetically restrained7 (Fig. 1c). How and why these distinct tumor evolutionary growth patterns emerge is not clear. Cell of origin, disease latency, strength and contingencies of the originating clonal driver(s), and the native and tumor microenvironment, together with underlying germline constraints, mutational processes and environmental carcinogens, may all play a role8. These have yet to be systematically investigated in the appropriate models.

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Fig. 1: Evolutionary trajectories in solid tumors and relationship to clinical course.

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Acknowledgements

Research support by CA179991 and CA220508 to C.A.I.D., who also receives research support from Bristol-Myers Squibb. K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award (grant reference number MR/P014712/1). C.S. is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169,FC001202), the UK Medical Research Council (FC001169, FC001202), and the Wellcome Trust (FC001169, FC001202) and from Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID16584) and the Breast Cancer Research Foundation (BCRF), European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement n°FP7 – 617844 (PROTEUS) and Marie Curie Network PloidyNet.

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Authors and Affiliations

  1. David M. Rubenstein Center for Pancreatic Cancer Research, Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Christine A. Iacobuzio-Donahue

  2. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O’Gorman Building, London, UK

    Kevin Litchfield & Charles Swanton

  3. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK

    Kevin Litchfield & Charles Swanton

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  1. Christine A. Iacobuzio-Donahue
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Correspondence to Christine A. Iacobuzio-Donahue or Charles Swanton.

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Iacobuzio-Donahue, C.A., Litchfield, K. & Swanton, C. Intratumor heterogeneity reflects clinical disease course. Nat Cancer 1, 3–6 (2020). https://doi.org/10.1038/s43018-019-0002-1

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