J Natl Cancer Inst. 2019 Oct 1;111(10):1068-1077. doi: 10.1093/jnci/djz005.
Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete.
To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases.
In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry.
Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.
肢端黑色素瘤是一种罕见的黑色素瘤，影响着世界各地的人群，无论肤色如何，其存活率均低于其他皮肤黑色素瘤。它的单核苷酸突变相对较少，没有皮肤黑色素瘤的 UV 特征，但具有以结构重排和扩增为特征的遗传特征。BRAF 突变的发生率低于其他皮肤黑色素瘤，而对替代治疗靶点的了解并不完整。
为了确定替代治疗靶点，我们对 122 例肢端黑色素瘤进行了靶向深度测序。我们在选择的病例中通过免疫组织化学证实了肿瘤抑制因子 p16 和 NF1 的缺失。
除了 BRAF（21.3%）、NRAS（27.9%）和 KIT（11.5%）突变外，我们还发现了广泛的 MAPK 通路激活改变，包括 BRAF（2.5%）、NTRK3（2.5%）、ALK（0.8%）和 PRKCA（0.8%）的融合，这些融合可以通过现有的抑制剂靶向。18 例（14.8%）存在 NF1 失活。NF1 协同因子 SPRED1 的失活发生在 8 例（6.6%）中，作为破坏 RAS 负调节的替代机制。扩增经常影响包含 PAK1 和 GAB2（n=27，22.1%）、CDK4（n=27，22.1%）、CCND1（n=24，19.7%）、EP300（n=20，16.4%）、YAP1（n=15，12.3%）、MDM2（n=13，10.7%）和 TERT（n=13，10.7%）的狭窄基因座，为治疗提供了额外的、可能互补的靶点。携带 BRAFV600E 突变的肢端黑色素瘤基因组扩增较少，且更常见于欧洲血统的患者。
我们的研究结果支持肢端黑色素瘤的一种新的、基于分子的亚分类，具有潜在的治疗意义：BRAFV600E 突变的肢端黑色素瘤与非肢端黑色素瘤具有相似的特征，可受益于 BRAF 抑制剂治疗，而非 BRAFV600E 突变的肢端黑色素瘤。非 BRAFV600E 突变的肢端黑色素瘤具有广泛的治疗相关改变。扩大分子谱分析将提高对这种肢端黑色素瘤亚型潜在靶向改变的检测。
