  From patients and physicians perspectives, the clinical definition of a tumor
malignant phenotype could be restricted to the early diagnosis of sub-types of
malignancies with the increased risk of existing therapy failure and high
likelihood of death from cancer. It is the viewpoint from which the
understanding of malignant regulatory signatures is considered in this
contribution. Analyses from this perspective of experimental and clinical
observations revealed the pivotal role of human stem cell-associated retroviral
sequences (SCARS) in the origin and pathophysiology of clinically-lethal
malignancies. SCARS represent evolutionary- and biologically-related family of
genomic regulatory sequences, the principal physiological function of which is
to create and maintain the stemness phenotype during human preimplantation
embryogenesis. SCARS expression must be silenced during cellular
differentiation and SCARS activity remains silent in most
terminally-differentiated human cells performing specialized functions in the
human body. De-repression and sustained activation of SCARS result in
differentiation-defective phenotypes, tissue- and organ-specific clinical
manifestations of which are diagnosed as pathological conditions defined by a
consensus of pathomorphological, molecular, and genetic examinations as the
malignant growth. Contemporary evidence are presented that high-fidelity
molecular signals of continuing activities of SCARS in association with genomic
regulatory networks of thousands functionally-active enhancers triggering
engagements of down-stream genetic loci may serve as both reliable diagnostic
tools and druggable molecular targets readily amenable for diagnosis and
efficient therapeutic management of clinically-lethal malignancies.
