Abstract：
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.
摘要：
尽管在治疗皮肤黑色素瘤方面取得了进展，肢端和粘膜(A/M)黑色素瘤患者的治疗选择仍然有限,预后较差.我们分析了156例黑色素瘤（101例皮肤，28肢，和27粘膜）使用FoundationOne癌症基因特异性临床测试平台，并确定了新的，A/M黑色素瘤特定解剖部位的潜在靶向基因组改变（GA）。使用新的A/M黑色素瘤临床前模型，我们证明了与皮肤黑素瘤相关的几种GA和相应的致癌途径在A/M黑素瘤中具有相似的靶向性。其他改动,包括MYC和CRKL扩增，是A/M黑色素瘤特有的，并且对使用BRD4抑制剂JQ1或Src/ABL抑制剂达沙替尼的间接靶向敏感，分别。我们进一步确定了新的，可操作的A/M特定更改，包括体内对达沙替尼反应的粘膜黑色素瘤中NF2融合失活。我们的研究强调了皮肤和A/M黑色素瘤之间新的分子差异，在A/M内的不同解剖部位，这可能会改变这些罕见黑素瘤的临床试验和治疗模式。
