背景:皮肤黑色素瘤(CM)是白种人中最常见的类型,而肢端黑色素瘤(AM)和粘膜黑色素瘤(MM),对免疫疗法和BRAF/MEK靶向疗法有抗性,在东亚人中更为常见。基因组分析对于治疗黑色素瘤至关重要,但日本缺乏这样的数据。
方法:分析了癌症基因组学和高级治疗学中心(C-CAT)编制的综合基因组分析数据。
结果:共分析了380例黑色素瘤,包括136厘米,46AM,168MM,和30葡萄膜黑色素瘤(UM)。MM包括结膜,鼻窦,口服,食道,肛门直肠,和外阴阴道黑素瘤.CM的中位肿瘤突变负荷(TMB)没有显着差异(3.39突变/兆碱基),上午(2.76),MM(3.78)是关键发现。在一例中发现了微卫星不稳定性-高状态。仅在45例患者中发现BRAFV600E/K(12%)。CM中的关键驱动突变是BRAF(38%),NRAS(21%),NF1(8%),和KIT(10%),CDKN2A的拷贝数改变(CNAs)频繁,CDKN2B,MYCAM的特征是改变了KIT(30%),NRAS(26%),NF1(11%)和CDKN2A,CDKN2B,CDK4、MDM2和CCND1CNAs。MM的特征是NRAS改变(24%),KIT(21%),NF1(17%)和MYC,KIT,和CDKN2ACNAs,基于解剖位置的差异。UM具有GNAQ或GNA11驱动突变(87%)和SF3B1或BAP1中的频繁突变。
结论:日本患者的独特基因组图谱,包括较低的TMB,与高加索人相比,与较差的治疗结果相关。该结果强调需要更有效的治疗剂。
BACKGROUND: 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.
METHODS: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed.
RESULTS: 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.
CONCLUSIONS: 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.