Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic pro
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CASE REPORT
Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic progression Erin M. Taylor1, Stephanie D. Byrum1, Jacob L. Edmondson1, Christopher P. Wardell2, Brittany G. Griffin3, Sara C. Shalin4, Murat Gokden4, Issam Makhoul5, Alan J. Tackett1 and Analiz Rodriguez3*
Abstract Melanoma brain metastases (MBM) portend a grim prognosis and can occur in up to 40% of melanoma patients. Genomic characterization of brain metastases has been previously carried out to identify potential mutational drivers. However, to date a comprehensive multi-omics approach has yet to be used to analyze brain metastases. In this case report, we present an unbiased proteogenomics analyses of a patient’s primary skin cancer and three brain metastases from distinct anatomic locations. We performed molecular profiling comprised of a targeted DNA panel and full transcriptome as well as proteomics using mass spectrometry. Phylogeny demonstrated that all MBMs shared a SMARCA4 mutation and deletion of 12q. Proteogenomics identified multiple pathways upregulated in the MBMs compared to the primary tumor. The protein, PIK3CG, was present in many of these pathways and had increased gene expression in metastatic melanoma tissue from the cancer genome atlas data. Proteomics demonstrated PIK3CG levels were significantly increased in all 3 MBMs and this finding was further validated by immunohistochemistry. In summary, this case report highlights the potential role of proteogenomics in identifying pathways involved in metastatic tumor progression. Furthermore, our multi-omics approach can be considered to aid in precision oncology efforts and provide avenues for therapeutic innovation. Keywords: Melanoma, Brain metastases, Proteomics, Proteogenomics, Multi-omics, PIK3CG Introduction In various cancer patient cohorts, the development of brain metastases (BM) is present in 24–45% of patients. Melanoma is one of the most common primary cancers to lead to BM. It is expected that 100,350 melanoma cases will be diagnosed in the US in 2020 and 6850 will die with metastatic disease [1]. Of those, up to 40% develop melanoma brain metastases (MBM) and up to 80% of patients have evidence of MBM upon autopsy. MBM is the leading cause of death in these patients and portends *Correspondence: [email protected] 3 Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Full list of author information is available at the end of the article
a median survival of less than a year [2, 3]. More research is needed in understanding mechanisms of melanoma metastatic progression to the brain. It is known that metastatic cancer cells continue to evolve following hematogenous spread and can acquire new mutations [4]. Genomic characterization of BMs and their respective primary tumors demonstrate potential clinically actionable genetic alterations are present in BM in approximately 50% of samples. However, even in a previously reported large cohort of 86 p
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