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Lineage dependency and lineage-survival oncogenes in human cancer

Nature Reviews Cancer volume 6, pages 593–602 (2006)Cite this article

An Erratum to this article was published on 01 September 2006

Key Points

  • The close association between cell lineage and cancer phenotype has long been recognized. This link raises the possibility that cellular mechanisms that govern lineage proliferation and survival during development might also underlie tumorigenic mechanisms.

  • Many somatic genetic alterations show lineage-restricted patterns across human tumours, which indicates that genetic changes in cancer might be conditioned by the lineage programmes that are embedded in tumour precursor cells.

  • A convergence of lineage-based and genetic observations gives rise to a lineage-dependency (or lineage-addiction) model of human cancer, wherein tumour cells depend crucially on survival mechanisms that are programmed into lineage precursor cells during development, which might be affected by acquired genetic alterations. Unlike oncogene addiction, which invokes a dependency on a tumour-specific gain-of-function event, lineage addiction involves the persistence and/or deregulation of crucial lineage-survival mechanisms during carcinogenesis or tumour progression.

  • Presumably, lineage-dependency mechanisms that promote tumour progression involve master regulatory genes that also exert key developmental survival roles. Such genes can be termed lineage-survival oncogenes.

  • MITF (microphthalmia-associated transcription factor) and the androgen receptor are prototype lineage-survival oncogenes in melanoma and prostate cancer, respectively. A review of the scientific literature readily identifies several more genes with presumptive or predicted lineage-survival functions in different cancers.

  • Recognition of the lineage-dependency model might expand existing paradigms for tumour biology by emphasizing the importance of lineage in shaping key oncogenic mechanisms, thereby offering an explanatory framework for the distribution of genetic alterations in cancer. Targeting lineage dependencies as well as classical gain-of-function events might require combinatorial or synthetic-lethal therapeutic approaches to cancer.

Abstract

Although cell-lineage and differentiation models dominate tumour classification and treatment, the recognition that cancer is also a genomic disease has prompted a reconfiguration of cancer taxonomies according to molecular criteria. Recent evidence indicates that a synthesis of lineage-based and genetic paradigms might offer new insights into crucial and therapeutically pliable tumour dependencies. For example, MITF (microphthalmia-associated transcription factor), which is a master regulator of the melanocyte lineage, might become a melanoma oncogene when deregulated in certain genetic contexts. MITF and other lineage-survival genes therefore implicate lineage dependency (or lineage addiction) as a newly recognized mechanism that is affected by tumour genetic alterations.

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Figure 1: Aberrant lineage ontogeny and somatic genetics in human tumour formation.
Figure 2: Lineage-restricted patterns of activating oncogene mutations in human solid tumours.
Figure 3: A lineage-dependency model for human cancer.
Figure 4: Therapeutic implications of tumour lineage dependency.

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Acknowledgements

This work was supported by grants from the US National Cancer Institute to L.A.G. and W.R.S.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Levi A. Garraway & William R. Sellers

  2. Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Levi A. Garraway

  3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Levi A. Garraway

  4. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Levi A. Garraway

  5. The Broad Institute of Harvard and MIT, Cambridge, 02141, Massachusetts, USA

    Levi A. Garraway

  6. Novartis Institutes for Biomedical Research Inc., Cambridge, 02139, Massachusetts, USA

    William R. Sellers

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Correspondence to Levi A. Garraway.

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W.R.S. is employed by the Novartis Institutes of Biomedical Research Inc., Cambridge, USA.

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Glossary

p16–CDK4–RB pathway

A vital cell-cycle checkpoint that operates in mammalian cells. The p16 protein (encoded by CDKN2A) is a well-characterized cell-cycle inhibitor, and the RB (Retinoblastoma) protein was one of the first tumour suppressors to be described.

Synthetic dosage lethality

A genetic interaction in which overexpression or activation of one gene or pathway becomes lethal to the cell when a second (normally non-lethal) mutation is also present.

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Garraway, L., Sellers, W. Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 6, 593–602 (2006). https://doi.org/10.1038/nrc1947

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