Integrated Analysis of Molecular and Clinical Features in Melanoma Patients with Brain Metastases

Swaminathan Kumar, MS (Advisor: Michael Davies, MD, PhD)

          Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with bulk RNA-seq data generated from their MBMs. On univariate analysis, the expression of multiple immune gene signatures was associated with improved OS. The gene expression signatures of several immune cell types positively correlated with OS, except for higher neutrophil gene expression which correlated with shorter OS. Univariate analysis of clinical features identified a low Karnofsky performance score (KPS), elevated serum lactate dehydrogenase (LDH), the presence of extracranial metastases (ECMs), and uncontrolled (versus controlled) ECMs as clinical predictors of shorter survival. Multivariate analyses were performed with significant clinical factors and immune features with no correlated variables in the model. After backward selection algorithm, the multivariable coxPH model identified low KPS, low T cell signature, and low monocytic lineage signature as independent predictors of shorter survival. Comparative analysis of MBMs from patients with MBMs only showed that these tumors were characterized by decreased oxidative phosphorylation (OXPHOS) and increased immune infiltration signatures compared to MBMs from patients with concurrent ECMs. To further characterize the role of OXPHOS in MBM progression, intra-patient heterogeneity of OXPHOS was studied using bulk RNA-seq data on 24 samples from 10 patients, who had multiple distinct MBMs. The intra-tumor heterogeneity of OXPHOS in MBMs was defined at the transcriptomic level using single-cell RNA-seq, single-nuclei RNA-seq, and spatial transcriptomics (ST) technologies. Together these results support the clinical significance of specific molecular and immune features of MBMs and suggest their potential use for developing reliable biomarkers and rational therapeutic combinations to improve patient outcomes.

Advisory Committee:

• Michael Davies, MD, PhD, Chair
• Jeffrey Chang, PhD
• Ken Chen, PhD
• Lawrence Kwong, PhD
• Ziyi Li, PhD

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