Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.
Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan.
Int J Clin Oncol. 2024 Dec;29(12):1984-1998. doi: 10.1007/s10147-024-02615-y. Epub 2024 Sep 9.
Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan.
Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed.
A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1.
The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.
在白种人中，最常见的皮肤黑色素瘤（CM），而肢端黑色素瘤（AM）和黏膜黑色素瘤（MM）对免疫疗法和 BRAF/MEK 靶向治疗具有抗性，在东亚人群中更为常见。基因组分析对于治疗黑色素瘤至关重要，但日本缺乏此类数据。
分析了在癌症基因组和先进治疗中心（C-CAT）汇编的综合基因组分析数据。
共分析了 380 例黑色素瘤，包括 136 例 CM、46 例 AM、168 例 MM 和 30 例葡萄膜黑色素瘤（UM）。MM 包括结膜、鼻旁窦、口腔、食管、肛门直肠和外阴阴道黑色素瘤。CM（3.39 个突变/兆碱基）、AM（2.76）和 MM（3.78）的中位肿瘤突变负荷（TMB）无显著差异，这是关键发现。一个病例存在微卫星不稳定高状态。仅在 45 例患者（12%）中发现 BRAF V600E/K。CM 的关键驱动基因突变包括 BRAF（38%）、NRAS（21%）、NF1（8%）和 KIT（10%），常伴有 CDKN2A、CDKN2B 和 MYC 的拷贝数改变（CNAs）。AM 的特点是 KIT（30%）、NRAS（26%）和 NF1（11%）改变以及 CDKN2A、CDKN2B、CDK4、MDM2 和 CCND1 的 CNA。MM 的特点是 NRAS（24%）、KIT（21%）和 NF1（17%）改变以及 MYC、KIT 和 CDKN2A 的 CNA，其位置不同。UM 具有 GNAQ 或 GNA11 驱动突变（87%）和 SF3B1 或 BAP1 的高频突变。
与白种人相比，日本患者的独特基因组分析结果，包括较低的 TMB，与较差的治疗结果相关。这一结果强调了需要更有效的治疗药物。
