Abstract
Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance.
Highlights
Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated
Since BRAF(V600E) activation requires a T>A transversion at nucleotide 1799, BRAF non-chronic sun-induced damage (CSD) mutations do not resemble nucleotide transitions typically found in sun-induced melanoma damage arising from cyclobutane pyrimidine dimers (CPDs) (Fig. 5b)
The non-CSD driver gene BRAF contains a high fraction of non-UV mutations deviating from exome-wide sample average; CSD drivers contain nucleotide transversions by cyclobutane pyrimidine dimers (CPDs) responsible for the initiation of the predominant C>T UV melanoma signature mutations
Summary
The emerging field of precision medicine has formalized our wish for a fast, efficient, and accurate course of action to maximize health benefits (Fig. 1, Box 1). In the past few years, systems biology has matured as a field and has established rules to design predictive, multiscale models Such systems biology models enable understanding of biochemical networks, discovery of biomarkers, and patient stratification based on unique genomic and non-genomic (e.g., transcriptomic, epigenomic, proteomic, metabolic) profiles. Master regulators present distinct vulnerabilities of networks Their identification is crucial for systemsbased rational drug design as well as for disease management by means of precision medicine. The molecular signatures of genomic and epigenomic changes will provide insight as to why melanoma stands out as such a serious and aggressive malignancy. This knowledge will impact our perspective on how to approach melanoma prevention, diagnosis, and therapy. We will provide examples of how systems biology- and genome biology-driven approaches to cancer accelerate our ability to understand and respond to malignant melanoma
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