Ulcerated Melanoma: Systems Biology Evidence of Inflammatory Imbalance Toward Pro?tumorigenicity

Abstract

Microscopic ulceration is an independent predictor of melanoma death. Here we used systems biology to query the role of host and tumor specific processes in defining the phenotype. Measures of systemic inflammation were predictive of fewer tumor infiltrating lymphocytes and poorer survival. Ulcerated melanomas were thicker and more mitotically active (transcriptomic upregulated cell-cycle pathways). Sequencing identified tumoral p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumors had perturbed expression of cytokine genes, consistent with protumorigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multi-omic data using neural networks highlighted a role for the ?-catenin pathway in the ulceration, linking genomic changes in the tumor to immunosuppression and cell proliferation. In summary the data suggest that ulceration is in part associated with genomic changes but that host factors predict melanoma death with evidence of reduced immune responses to the tumor.