Zhang Fenghao, Wu Xiaowen, Jiao Tao, Du Haizhen, Guo Qian, Cui Chuanliang, Chi Zhihong, Sheng Xinan, Jiang Dezhi, Zhang Yuhong, Wu Jiayan, Kong Yan, Si Lu
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Research Institute, Beijing 100142, China.
Beijing Kanghui Biotechnology Co. LTD, Beijing 100101, China.
J Genet Genomics. 2025 Apr;52(4):525-538. doi: 10.1016/j.jgg.2024.12.018. Epub 2025 Jan 9.
Acral melanoma, the most common melanoma subtype in East Asia, is associated with a poor prognosis. This study aims to comprehensively analyze the genomic characteristics of acral melanoma in East Asians. We conduct whole-genome sequencing of 55 acral melanoma tumors and perform data mining with relevant clinical data. Our findings reveal a unique mutational profile in East Asian acral melanoma, characterized by fewer point mutations and structural variations, a higher prevalence of NRAS mutations, and a lower frequency of BRAF mutations compared to patients of European descent. Notably, we identify previously underestimated ultraviolet radiation signatures and their significant association with BRAF and NRAS mutations. Structural rearrangement signatures indicate distinct mutational processes in BRAF-driven versus NRAS-driven tumors. We also find that homologous recombination deficiency with MAPK pathway mutations correlated with poor prognosis. The structural variations and amplifications in EP300, TERT, RAC1, and LZTR1 point to potential therapeutic targets tailored to East Asian populations. The high prevalence of whole-genome duplication events in BRAF/NRAS-mutated tumors suggests a synergistic carcinogenic effect that warrants further investigation. In summary, our study provides important insights into the genetic underpinnings of acral melanoma in East Asians, creating opportunities for targeted therapies.
肢端黑色素瘤是东亚地区最常见的黑色素瘤亚型，其预后较差。本研究旨在全面分析东亚人肢端黑色素瘤的基因组特征。我们对55例肢端黑色素瘤肿瘤进行了全基因组测序，并结合相关临床数据进行数据挖掘。我们的研究结果揭示了东亚肢端黑色素瘤独特的突变谱，其特点是与欧洲血统患者相比，点突变和结构变异较少，NRAS突变的发生率较高，BRAF突变的频率较低。值得注意的是，我们发现了以前被低估的紫外线辐射特征及其与BRAF和NRAS突变的显著关联。结构重排特征表明BRAF驱动与NRAS驱动的肿瘤中存在不同的突变过程。我们还发现，伴有丝裂原活化蛋白激酶（MAPK）通路突变的同源重组缺陷与预后不良相关。EP300、端粒酶逆转录酶（TERT）、RAC1和LZTR1中的结构变异和扩增指向了针对东亚人群的潜在治疗靶点。BRAF/NRAS突变肿瘤中全基因组复制事件的高发生率表明存在协同致癌作用，值得进一步研究。总之，我们的研究为东亚人肢端黑色素瘤的遗传基础提供了重要见解，为靶向治疗创造了机会。
