Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling
Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling
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通过靶向突变分析揭示肢端和粘膜黑色素瘤的独特基因组特征
DOI：
10.1111/pcmr.12865
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发表时间：
2020-01-27
影响因子：
4.3
通讯作者：
Liu, Baorui
中科院分区：
文献类型：
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作者：
Zou, Zhengyun;Ou, Qiuxiang;Liu, Baorui
包括中国在内，黑色素瘤的发病率在全球范围内都在上升。与高加索人相比，中国人非皮肤黑色素瘤的发病率明显更高。在这里，我们对89例中国人手术切除的原发性黑色素瘤进行了基因组图谱分析，包括肢端(n=54)、皮肤(n=22)和粘膜(n=13)，采用基于杂交捕获的下一代测序。我们发现，粘膜黑色素瘤往往比其他类型的黑色素瘤具有更多的致病突变，尽管这一发现的生物学意义仍不确定。包括6q、9p和10p/q丢失在内的染色体臂水平改变在所有亚型中都是高度复发的，但粘膜黑色素瘤与基因组不稳定性的增加显著相关。重要的是，7P的增加与非皮肤黑色素瘤的不良临床结果显著相关，是这些亚型中一个有趣的预后生物标记物。此外，4Q12(KIT、KDR和PDGFRα)的局部扩增和RAD51缺失在粘膜黑色素瘤中更为丰富，而NOTCH2扩增在肢端黑色素瘤中更为丰富。此外，皮肤黑色素瘤的突变负荷高于肢端黑色素瘤，而粘膜黑色素瘤在突变负荷上与其他亚型没有区别。总之，我们的数据揭示了中国人肢端和粘膜黑色素瘤的重要特征，包括独特的驱动突变模式和增加的基因组不稳定性。这些发现突出了联合疗法在黑色素瘤临床治疗中的可能性。
The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non-cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture-based next-generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm-level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non-cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFR alpha) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.