Arnoff Taylor E, El-Deiry Wafik S
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University Providence, RI, USA.
Hematology/Oncology Division, Department of Medicine, Lifespan Health System and The Warren Alpert Medical School, Brown University Providence, RI, USA.
Am J Cancer Res. 2022 May 15;12(5):2102-2117. eCollection 2022.
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 and amplifications compared to primary disease, and amplifications are associated with lower overall survival. amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, and , 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 may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors. Patients with amplification display deep deletions in , alterations also associated with a higher rate of metastasis to the brain. Patients with a deletion have a higher rate of alterations in , and , alterations previously associated with favorable response to immune-checkpoint inhibitors in melanoma. We propose alteration as a potential biomarker to predict response to immunotherapy in melanoma. We found that GBM displays the highest rate of amplifications (9.63%) and deletions (54.39%) across all cancer types. In 592 GBM samples we found that 8.45% display amplification. We suggest that patients with melanoma or GBM and amplifications in and alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.
转移性黑色素瘤的五年生存率约为10%，预测转移至特定解剖部位的生物标志物或针对转移灶的靶向治疗较为匮乏。我们分析了1015例原发性黑色素瘤和358例转移性黑色素瘤，发现与原发性疾病相比，转移性疾病中 和 扩增更为富集，且 扩增与较低的总生存率相关。 扩增与脑和肝转移率较高相关。与原发性疾病相比，转移性黑色素瘤中两个p53负调节因子 和 也发生了改变。这些发现表明，与原发性疾病相比，转移性黑色素瘤患者的TP53信号通路失调。我们提出，转移性黑色素瘤且 野生型的患者可能更有可能从MDM2、MDM4、USP7和PPM1D抑制剂中获益。 扩增的患者在 中显示深度缺失，这种改变也与较高的脑转移率相关。 缺失的患者在 和 中改变率较高，这些改变先前与黑色素瘤对免疫检查点抑制剂的良好反应相关。我们提出 改变作为预测黑色素瘤免疫治疗反应的潜在生物标志物。我们发现，在所有癌症类型中，胶质母细胞瘤（GBM）的 扩增率（9.63%）和 缺失率（54.39%）最高。在592例GBM样本中，我们发现8.45%显示 扩增。我们建议，黑色素瘤或GBM患者以及 和 改变有扩增的患者可能从MDM2/4和CDK4/6靶向抑制剂联合免疫治疗中获益。
