Lineage dependency and lineage-survival oncogenes in human cancer

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.