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Genomic and phenotypic heterogeneity in prostate cancer

Nature Reviews Urology volume 18, pages 79–92 (2021)Cite this article

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Abstract

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.

Key points

  • Primary prostate cancers are often multifocal with spatial and morphologically distinct tumour foci.

  • Individual tumour foci can show non-overlapping truncal genomic alterations, suggesting that multiple clonally distinct cancers can arise in a given patient.

  • Intra-tumoural and inter-tumoural heterogeneity present within the prostate gland poses diagnostic challenges.

  • Despite the multiclonality of primary cancer, clonal bottlenecks imposed by the metastatic process and further by therapeutic interventions seem to select for a single dominant clone in lethal metastatic prostate cancer.

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Fig. 1: Model of clonal progression of prostate cancer.
Fig. 2: Visualizing clonal and subclonal heterogeneity in tumour tissues.
Fig. 3: Multifocal prostate cancer.
Fig. 4: Morphological heterogeneity in mCRPC.
Fig. 5: Schematic of scenarios of clonal evolution of metastatic prostate cancer.

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Acknowledgements

The authors thank C. Morrissey (University of Washington), T. Lotan (Johns Hopkins School of Medicine) and W. B. Isaacs (Johns Hopkins School of Medicine), as well as members of the Haffner, Yegnasubramanian and Nelson laboratories, for valuable discussions and suggestions on the manuscript. This work of the authors is supported by the NIH/NCI (P50CA097186, P50CA58236, U01 CA196390, P30 CA006973, R01CA183965), the US Department of Defense Prostate Cancer Research Program (W81XWH-20-1-0111, W81XWH-18-1-0406, W81XWH-18-2-0015), the Prostate Cancer Foundation, the Safeway Foundation, the Commonwealth Foundation and the Irving Hansen Memorial Foundation.

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Authors and Affiliations

  1. Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Michael C. Haffner & Peter S. Nelson

  2. Department of Pathology, University of Washington, Seattle, WA, USA

    Michael C. Haffner & Lawrence D. True

  3. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael C. Haffner, William G. Nelson, Jonathan I. Epstein & Angelo M. De Marzo

  4. Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands

    Wilbert Zwart

  5. Department of Urology, University of Washington, Seattle, WA, USA

    Martine P. Roudier

  6. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    William G. Nelson, Jonathan I. Epstein, Angelo M. De Marzo & Srinivasan Yegnasubramanian

  7. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    William G. Nelson, Jonathan I. Epstein & Angelo M. De Marzo

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Contributions

M.C.H., J.I.E., P.S.N. and S.Y. researched data for the article, made a substantial contribution to discussion of content, wrote and reviewed/edited the manuscript before submission. W.Z. and M.P.R. researched data for the article, made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. L.D.T. reviewed/edited the manuscript before submission. W.G.N. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. A.M.D.M. made a substantial contribution to discussion of content, wrote and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Michael C. Haffner.

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Competing interests

S.Y., W.G.N. and A.M.D.M. are paid consultants to and received sponsored research funding from Cepheid. S.Y. and W.G.N. are co-inventors of intellectual property describing the use of DNA methylation changes as prostate cancer biomarkers and are eligible to earn royalties related to the future sale of any products using those technologies. S.Y. and A.M.D.M. receive sponsored research funding from Janssen. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no competing interests.

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Nature Reviews Urology thanks Mark Rubin, Kent Mouw and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Inter-patient heterogeneity

Differences in tumour genotypes and phenotypes between individual patients.

Intra-tumoural heterogeneity

Genomic, epigenetic, transcriptomic and phenotypic differences within a tumour mass.

Inter-tumoural heterogeneity

Differences between anatomically distinct tumour sites within a given patient.

Multifocality

Spatially distinct and often histomorphologically different tumour lesions within one affected organ.

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Haffner, M.C., Zwart, W., Roudier, M.P. et al. Genomic and phenotypic heterogeneity in prostate cancer. Nat Rev Urol 18, 79–92 (2021). https://doi.org/10.1038/s41585-020-00400-w

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