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From patients and physicians perspectives, the clinical definition of a tumormalignant phenotype could be restricted to the early diagnosis of sub-types ofmalignancies with the increased risk of existing therapy failure and highlikelihood of death from cancer. It is the viewpoint from which theunderstanding of malignant regulatory signatures is considered in thiscontribution. Analyses from this perspective of experimental and clinicalobservations revealed the pivotal role of human stem cell-associated retroviralsequences (SCARS) in the origin and pathophysiology of clinically-lethalmalignancies. SCARS represent evolutionary- and biologically-related family ofgenomic regulatory sequences, the principal physiological function of which isto create and maintain the stemness phenotype during human preimplantationembryogenesis. SCARS expression must be silenced during cellulardifferentiation and SCARS activity remains silent in mostterminally-differentiated human cells performing specialized functions in thehuman body. De-repression and sustained activation of SCARS result indifferentiation-defective phenotypes, tissue- and organ-specific clinicalmanifestations of which are diagnosed as pathological conditions defined by aconsensus of pathomorphological, molecular, and genetic examinations as themalignant growth. Contemporary evidence are presented that high-fidelitymolecular signals of continuing activities of SCARS in association with genomicregulatory networks of thousands functionally-active enhancers triggeringengagements of down-stream genetic loci may serve as both reliable diagnostictools and druggable molecular targets readily amenable for diagnosis andefficient therapeutic management of clinically-lethal malignancies.

Genomics-guided drawing of malignant regulatory signatures revealed a  pivotal role of human stem cell-associated retroviral sequences (SCARS) and  functionally-active hESC enhancers