Melanoma is the most serious type of
skin cancer that frequently spreads to other organs of the human body. Especially
melanoma metastases to the brain (intracranial
metastases) are hard to treat and a major cause of death of
melanoma patients. Little is known about molecular alterations and altered mechanisms that distinguish intra- from extracranial
melanoma metastases. So far, almost all existing studies compared intracranial
metastases from one set of patients to extracranial
metastases of an another set of
melanoma patients. This neglects the important facts that each
melanoma is highly individual and that intra- and extracranial
melanoma metastases from the same patient are more similar to each other than to
melanoma metastases from other patients in the same organ. To overcome this, we compared the gene expression profiles of 16 intracranial
metastases to their corresponding 21 patient-matched extracranial
metastases in a personalized way using a three-state Hidden Markov Model (HMM) to identify altered genes for each individual
metastasis pair. This enabled three major findings by considering the predicted gene expression alterations across all patients: (i) most frequently altered pathways include
cytokine-receptor interaction, calcium signaling, ECM-receptor interaction, cAMP signaling, Jak-STAT and PI3K/Akt signaling, (ii) immune-relevant signaling pathway genes were downregulated in intracranial
metastases, and (iii) intracranial
metastases were associated with a brain-like phenotype gene expression program. Further, the integration of all differentially expressed genes across the patient-matched
melanoma metastasis pairs led to a set of 103 genes that were consistently down- or up-regulated in at least 11 of the 16 of the patients. This set of genes contained many genes involved in the regulation of immune responses, cell growth, cellular signaling and transport processes. An analysis of these genes in the TCGA
melanoma cohort showed that the expression behavior of 11 genes was significantly associated with survival. Moreover, a comparison of the 103 genes to three closely related
melanoma metastasis studies revealed a core set of eight genes that were consistently down- or upregulated in intra- compared to extracranial
metastases in at least two of the three related studies (down: CILP, DPT, FGF7, LAMP3, MEOX2, TMEM119; up: GLDN, PMP2) including FGF7 that was also significantly associated with survival. Our findings contribute to a better characterization of genes and pathways that distinguish intra- from extracranial
melanoma metastasis and provide important hints for future experimental studies to identify potential targets for new therapeutic approaches.