RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors
RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors
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DOI：
10.1200/jco.2011.36.7680
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发表时间：
2012-01-20
影响因子：
45.3
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
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作者：
Oberholzer, Patrick A.;Kee, Damien;Garraway, Levi A.
目的RAF抑制剂对BRAF V600E突变的黑色素瘤有效，但可诱发角化棘皮瘤(KAS)和皮肤鳞状细胞癌(CSCs)。这些药物促进继发性恶性肿瘤的潜力令人担忧。我们分析了CSCC和KA病变的基因突变，试图确定其形成的潜在机制。方法四个国际中心提供了237 KA或CSCC肿瘤样本，这些样本来自接受RAF抑制剂(维莫拉非尼或索拉非尼；n=19)或免疫抑制治疗(n=53)或自发发展的肿瘤(n=165)的患者。利用基于质谱学的基因分型平台，对每个样本进行了33个癌症相关基因的396个已知体细胞突变的分析。结果在16%的肿瘤中检测到突变(38/237)，其中5个肿瘤包含两个突变。先前在鳞状细胞肿瘤中发现了TP53、CDKN2A、HRAS、KRAS和PIK3CA的突变。首次发现MYC、FGFR3和VHL基因突变。在接受RAF抑制剂治疗的患者的肿瘤中，发现激活RAS突变的频率高于接受非RAF抑制剂治疗的患者(21.1%vs3.2%；P<；.01)，尽管治疗组之间的总体突变率相似(RAF抑制剂，21.1%；免疫抑制，18.9%；自发的，17.6%；P=不显著)。肿瘤组织学(KA和CSCC)、肿瘤部位(头颈部和其他)、患者年龄(70岁)和性别对突变率和类型没有显著影响。结论RAF抑制剂治疗患者的鳞状细胞肿瘤具有明显的突变特征，支持RAS诱导的细胞肿瘤发生机制。可以想象，MEK和RAF联合靶向治疗可以减少或预防这些肿瘤的形成。
PurposeRAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation.MethodsFour international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform.ResultsMutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (70 years), and sex had no significant impact on mutation rate or type.ConclusionSquamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.