尽管皮肤黑色素瘤的治疗取得了进展，但肢端和粘膜 (A/M) 黑色素瘤患者的治疗选择仍然有限且预后不佳。我们使用 Foundation One 癌症基因特异性临床测试平台分析了 156 个黑色素瘤（101 个皮肤黑色素瘤、28 个肢端黑色素瘤和 27 个粘膜黑色素瘤），并在 A/M 黑色素瘤的特定解剖部位发现了新的、潜在可靶向的基因组改变 (GA)。使用 A/M 黑色素瘤的新型临床前模型，我们证明与皮肤黑色素瘤相关的几种 GA 和相应的致癌途径在 A/M 黑色素瘤中同样是可靶向的。其他改变，包括 MYC 和 CRKL 扩增，是 A/M 黑色素瘤所特有的，并且容易分别使用 BRD4 抑制剂 JQ1 或 Src/ABL 抑制剂达沙替尼进行间接靶向。我们进一步鉴定了新的、可操作的 A/M 特异性改变，包括体内对达沙替尼有反应的粘膜黑色素瘤中的失活 NF2 融合。我们的研究强调了皮肤黑色素瘤和 A/M 黑色素瘤之间以及 A/M 内不同解剖部位之间的新分子差异，这可能会改变这些罕见黑色素瘤的临床测试和治疗范例。© 2024 UICC。

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.© 2024 UICC.