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摘要: 黑色素瘤是一种发病率极高、极难治愈的皮肤恶性肿瘤, 其中转移性黑色素瘤的5年生存率几乎为零。虽然化疗和免疫疗法(如抗PD-1/PD-L1单克隆抗体生物制剂)发展迅速, 药物抵抗的高发率仍是治愈率低的主要问题。因此, 目前研究热点逐渐转移至"运用生物标志物进行早期辅助诊断和药物反应预测"。随着检测技术的日新月异, 很多新型生物标志物被发现, 甚至已作为治疗靶点。本文从基因水平和表观遗传学水平总结黑色素瘤的生物标志物研究进展, 并讨论其对疾病诊断、发展和治疗反应的预测价值, 为寻找潜在治疗靶点提供新的思路。Abstract: Melanoma is one of the most aggressive cutaneous malignancies with an increasing incidence in recent decades, especially in western countries. It is considered to be an incurable disease, and patients with metastatic melanoma survive no more than 5 years. Despite rapid improvement in chemotherapy and immunotherapy, such as anti-PD-1/PD-L1 treatment, the high frequency of drug resistance remains a difficult problem. Thus, recent research has shifted slightly to the field of biomarkers to achieve the more urgent goal of aiding in the diagnosis and predicting response and resistance to therapy. With the development of fascinating technologies in laboratory testing, numerous novel biomarkers have been identified, and some of them exhibit potential as therapeutic targets. In this review, we summarize the latest genetic and epigenetic biomarkers, discuss their role in the prediction of disease progression and response to therapies, and provide insights into potential targets for future therapies.
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Key words:
- melanoma /
- PD-1 /
- 5-hydroxymethylated cytosine /
- micro-RNA /
- long non-coding RNA
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表 1 黑色素瘤靶向治疗的基因生物标志物
基因生物标志物 发生率 治疗干预 参考文献 BRAF(V600 E/K) 40%~60% 维洛菲尼或达拉菲尼(联合MEK抑制剂，称为曲美替尼) [12-15] BRAF(非V600E/K) 5% BRAF抑制物联合维洛菲尼或达拉菲尼联合或不联合MEK抑制剂, 临床试验中 [16-17] NRAS 20% MEK抑制物CDK4/6抑制物的临床试验 [18] NF1 46%野生型BRAF和NRAS MAPK抑制物，尚处在评估中 [19] KIT 28%~39%黏膜、肢端或慢性光损伤皮肤 伊马替尼、尼洛替尼或其他KIT-靶向抑制物 [20] TP53/CDKN2A 11% CDK4/6抑制物, 早期临床试验中 [21] 基因表达图谱 — 预示着对白细胞介素-2应答 [22] 
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表 2 黑色素瘤中高甲基化的基因
基因 与黑色素瘤的相关性 文献 LINE-1 与转移相关 [36] CLDN11 导致肿瘤相关基因失活 [38] TERT, MGMT, KIT, TNF, MITF 与临床特征相关 [42-43] RASSF6, RASSF10 转移性黑色素瘤中可看到，抑制肿瘤细胞的侵袭 [46-47] GPX3 与黑色素瘤的发生相关 [48] MMP-9 肿瘤中过表达 [49] SYNPO2 肿瘤中表达降低 [50] CDKN1C 通过抑制细胞周期蛋白CDK阻止细胞周期的G1期 [51-52] LXN 抑制细胞增生 [51] ASC/PYCARDC/PYCARD 通过减少IKK α/β磷酸化抑制肿瘤产生 [53] SOCS1 降低细胞因子相关反应，阻止细胞周期G1/S和G1/M期，与CDH1相关 [54] Caspase 8 与镉刺激细胞生长相关并抑制死亡通路 [55] CDH1 肿瘤分期越高，预后越差，表达越低 [56-57] MGMT 预示肿瘤细胞抵抗 [56] RAR-b2 肿瘤抑制基因 [56] CIITA-PIV 作用于IFN-γ通路 [57] SOCS2 减弱细胞因子相关反应 [57] TNFRSF10C (DcR1/2) 促使细胞保护性受体产生，免受TRAIL介导的细胞凋亡 [57] TPM1 调控actin介导的细胞移动 [57] TIMP3 主要负向调控血管生成 [57-58] CDKN2A 抑制CDK4和CDK6，活化pR8，阻止细胞周期G1期 [59] DPPIV 肿瘤患者血清中降低 [60-61] FRZB 转移抑制因子，阻止Wnt5a信号通路 [62-63] SOCS3 抑制白细胞介素-17/Stat3通路，在老鼠模型中抑制肿瘤生长 [64-65] THBS1 介导细胞与细胞以及细胞与基质相互作用，与血小板聚集和血管生成密切相关 [66] TM 与转化、进展相关，表达下降 [67]
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