A SYSTEMATIC INTEGRATIVE ANALYSIS AND FUNCTIONAL GENOMICS OF MELANOMA MAINTENANCE

Abstract

IN VIEW OF THE HIGHLY HETEROGENEOUS MUTATIONAL SIGNATURE OF MELANOMA, IT IS IMPORTANT TO DEVELOP SUCCESSFUL THERAPIES TO IDENTIFY COOPERATING ONCOGENES AND RECONSTITUTE THE GENOMIC ARCHITECTURE THAT DRIVES THEIR SYNERGISTIC EFFECTS. I INVESTIGATED THE SYSTEMS BIOLOGY OF A TUMOR?S FUNCTIONAL MAINTENANCE IN MELANOMA AS DEFINED BY HARDWIRED SOMATIC MUTATIONS. INTEGRATIVE ANALYSIS AND FUNCTIONAL VALIDATION IN ONE MELANOMA PATIENT WITH A COMPLEX SET OF TUMORS AND CELL LINES CONFIRMED THE BIOLOGICAL SIGNIFICANCE OF THESE SOMATIC EVENTS, AND SUGGESTED THE PRESENCE OF A FUNCTIONAL MODULE. A MAINTENANCE FUNCTIONAL MODULE IS DEFINED AS A CORE SET OF SOMATIC EVENTS PERSISTING THROUGHOUT THE TUMOR EVOLUTION OF ANY MELANOMA PATIENT, PERFORMING IN A COOPERATIVE MANNER WITH SIGNIFICANT EFFECT ON TUMOR PROLIFERATION. FINALLY, I DISCOVERED A UNIVERSAL FUNCTIONAL MODULE IN MELANOMA. THE SIGNIFICANT ENRICHMENT OF THIS MODULE ON SEVERAL CHROMOSOMAL SEGMENTS SUGGESTS THE IMPORTANCE OF THESE SEGMENTS HARBOR