<i>MDM2/MDM4</i> amplification and <i>CDKN2A</i> deletion in metastatic melanoma and glioblastoma multiforme may have implications for targeted therapeutics and immunotherapy.

Abstract

Metastatic melanoma has a five-year survival of ~10%, with a paucity of biomarkers predicting metastasis to specific anatomic sites or targeted therapies for metastases. We analyzed 1015 primary and 358 metastatic melanomas and found metastatic disease is enriched for <i>MDM2</i> and <i>MDM4</i> amplifications compared to primary disease, and amplifications are associated with lower overall survival. <i>MDM2/4</i> amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, <i>USP7</i> and <i>PPM1D</i>, are also altered in metastatic melanoma compared to primary disease. These findings suggest that patients with metastatic melanoma have a dysregulated TP53 pathway compared to primary disease. We propose that patients with metastatic melanoma and wild-type <i>TP53</i> may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors. Patients with <i>MDM2/4</i> amplification display deep deletions in <i>CDKN2A</i>, alterations also associated with a higher rate of metastasis to the brain. Patients with a <i>CDKN2A</i> deletion have a higher rate of alterations in <i>TTN, MUC16, LRP1B</i>, and <i>NF1</i>, alterations previously associated with favorable response to immune-checkpoint inhibitors in melanoma. We propose <i>CDKN2A</i> alteration as a potential biomarker to predict response to immunotherapy in melanoma. We found that GBM displays the highest rate of <i>MDM4</i> amplifications (9.63%) and <i>CDKN2A</i> deletions (54.39%) across all cancer types. In 592 GBM samples we found that 8.45% display <i>MDM2</i> amplification. We suggest that patients with melanoma or GBM and amplifications in <i>MDM2/4</i> and <i>CDKN2A</i> alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.