Abstract
Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour.
Highlights
Cutaneous melanoma is still increasing in incidence and mortality in many countries
This paper describes a systems biology investigation of host and multiomic tumour variables associated with the phenotype which identified potentially actionable host factors playing a role in ulceration and highlights the significance of β-catenin signalling in aggressive melanoma
The study's strengths were that two large independent data sets were available to explore host factors and the larger data set, the Leeds Melanoma Cohort (LMC) benefitted from multi-omic tumour data from a large number of primary tumours
Summary
Cutaneous melanoma is still increasing in incidence and mortality in many countries. immunotherapy has improved outcomes for patients with advanced disease, 40% do not benefit, and the need to better understand the biology of the tumour and host variation in response remains crucial. We have reported evidence previously that ulceration may at least in part, be driven by host systemic inflammation in that obesity, diabetes, vitamin D deficiency and smoking were associated with ulceration, in the Leeds Melanoma Cohort (LMC) (Newton-Bishop et al, 2015). This hypothesis was subsequently supported by an Australian study in which ulceration in thick tumours was associated with diabetes, and that statin use (which is reported to reduce IL-6 levels (Sepehri et al, 2016)) was protective for ulceration (von Schuckmann et al, 2017). 2.4 | Measurement of circulating inflammatory markers and serum vitamin D from blood samples taken at recruitment to the study
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