Genetic alterations in primary melanoma in Taiwan
Genetic alterations in primary melanoma in Taiwan
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DOI：
10.1111/bjd.18425
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发表时间：
2019-10-15
影响因子：
10.3
通讯作者：
Chu, C-Y
中科院分区：
文献类型：
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作者：
Sheen, Y-S;Tan, K-T;Chu, C-Y
肢端黑色素瘤（AM）是亚洲人最常见的恶性黑色素瘤的组织病理学亚型。然而，亚洲人AM和非肢端皮肤黑色素瘤（NAM）的突变特征差异还不清楚。目的了解黑色素瘤不同亚型之间各种突变的患病率、模式和相关性。方法我们使用下一代测序技术对66例原发性黑色素瘤（包括45例AM和21例NAM）中的409个癌症相关基因进行了全面的基因组分析。结果大多数AM（n = 27/45; 60%），但21例NAM中只有5例（24%）为三重野生型（三重WT）肿瘤。与AM相比，NAM显示出显著更高的BRAF突变频率。AM中NRAS/KRAS突变、细胞周期畸变、BIRC 2、BIRC 3和BIRC 5拷贝数增加以及受体酪氨酸激酶基因增加的频率显著较高。在AM和NAM中发现溃疡发生率显著较高，伴有细胞周期畸变和受体酪氨酸激酶基因获得。值得注意的是，在66例黑色素瘤患者中，尤其是在45例AM患者中，BIRC 2、BIRC 3和BIRC 5的细胞周期畸变和拷贝数增加与黑色素瘤特异性生存率差显著相关。多因素分析显示淋巴结转移和细胞周期异常是影响黑色素瘤特异性生存的独立预后因素。结论本研究加强了我们对亚洲人AM和NAM致癌突变模式和临床相关性的理解。关于这个话题我们已经知道了什么？驱动基因的突变频率在黑色素瘤亚型之间变化。肢端黑色素瘤是亚洲人最常见的黑色素瘤亚型。KIT突变和拷贝数变异在肢端型黑色素瘤中比在非肢端型黑色素瘤中更常见。NRAS/KRAS突变、细胞周期畸变、BIRC 2、BIRC 3和BIRC 5的拷贝数增加以及受体酪氨酸激酶基因扩增在肢端黑色素瘤中显著富集，可能是治疗的潜在靶点。黑色素瘤细胞周期畸变和受体酪氨酸激酶基因的增益显着更可能包含溃疡。翻译的信息是什么？BIRC 2、BIRC 3和BIRC 5的细胞周期畸变和拷贝数增加与黑色素瘤特异性生存率差显著相关。这些观察结果应进一步探索，以用于未来的药物开发。
Background Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. Objectives To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. Methods We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. Results Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival. Conclusions This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic?Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add?NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message?Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.