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

Metastatic melanoma has a five-year survival of similar to 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 MDM2 and MDM4 amplifications compared to primary disease, and amplifications are associated with lower overall survival. MDM2/4 amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, USP7 and PPM1D, 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 TP53 may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors. Patients with MDM2/4 amplification display deep deletions in CDKN2A, alterations also associated with a higher rate of metastasis to the brain. Patients with a CDKN2A deletion have a higher rate of alterations in TTN, MUC16, LRP1B, and NF1, alterations previously associated with favorable response to immune-checkpoint inhibitors in melanoma. We propose CDKN2A alteration as a potential biomarker to predict response to immunotherapy in melanoma. We found that GBM displays the highest rate of MDM4 amplifications (9.63%) and CDKN2A deletions (54.39%) across all cancer types. In 592 GBM samples we found that 8.45% display MDM2 amplification. We suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.