Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases
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Gino K. In1, Kelsey Poorman2, Michelle Saul2, Steven O’Day3, Jeffrey M. Farma4, Anthony J. Olszanski4, Michael S. Gordon5, Jacob S. Thomas1,6, Burton Eisenberg6, Lawrence Flaherty7, Amy Weise7, Steven Daveluy7, Geoffrey Gibney8, Michael B. Atkins8 and Ari Vanderwalde9
1 USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
2 Caris Life Sciences, Phoenix, AZ, USA
3 John Wayne Cancer Institute, Santa Monica, CA, USA
4 Fox Chase Cancer Center, Philadelphia, PA, USA
5 HonorHealth Medical Group, Scottsdale, AZ, USA
6 Hoag Family Cancer Institute, Newport Beach, CA, USA
7 Karmanos Cancer Institute, Detroit, MI, USA
8 Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
9 University of Tennessee Health Science Center, West Cancer Center, Germantown, TN, USA
|Gino K. In,||email:||[email protected]|
Keywords: melanoma; brain metastases; BRAF; PD-L1; TMB
Received: March 25, 2020 Accepted: July 07, 2020 Published: August 18, 2020
Background: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases.
Materials and Methods: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM.
Results: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB (p = .04) and higher PD-L1 expression (p = .002), compared to PCM. PD-L1 expression was slightly higher among MBM compared to ECM (p = .042), but there was no difference between TMB (p = .21).
Conclusions: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.
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