Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Cancer Discov. 2013 Aug;3(8):862-9. doi: 10.1158/2159-8290.CD-13-0014. Epub 2013 Apr 23.
In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.
在多发性骨髓瘤中，针对致癌突变的特异性治疗靶向方面进展甚微。全基因组测序数据最近显示，一部分患者的 BRAF 激酶中存在激活突变（V600E）。为了揭示这种突变在多发性骨髓瘤中的临床相关性，我们将 379 名骨髓瘤患者的原发性肿瘤样本中的突变状态与疾病结果进行了相关性分析。与对照组相比，我们发现突变携带者发生髓外疾病的发生率明显更高，总生存期更短。最重要的是，我们报告了一例经证实存在 BRAF V600E 突变的复发性多发性骨髓瘤患者，该患者广泛发生髓外疾病，对所有已批准的治疗方案均耐药，而对低剂量的突变特异性 BRAF 抑制剂 vemurafenib 快速且持久地反应。总的来说，我们提供了 BRAF V600E 突变在克隆进化背景下发展的证据，并描述了这一可靶向突变的预后和治疗相关性。
