Spitz tumors and melanomas with MET fusion

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist. The UCSF dermatopathology array comparative genomic hybridizaton database consists of copy number profiles of difficult to classify tumors obtained in the course of clinical practice. These cases were noted to have either a copy number transition within MET with relative gain of the 3' end of the gene or gain of the distal portion of chromosome 7q. There are 6 cases in this series, with one replicate each.

致癌基因融合已在多种癌症中被发现，其中不少可作为治疗生物标志物或治疗靶点。本研究鉴定出6例不同的黑素细胞肿瘤，其基因组发生MET基因重排，将MET的激酶结构域与6种不同的N端伙伴基因进行框内融合。这些肿瘤在其他已确认的黑色素瘤致癌基因中未携带激活突变。我们对其中两种已鉴定的融合蛋白（TRIM4-MET与ZKSCAN1-MET）进行功能表征，发现它们可持续激活丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）、磷脂酰肌醇3-激酶（phosphoinositol-3 kinase, PI3K）以及磷脂酶Cγ1（phospholipase C gamma 1, PLCγ1）信号通路。MET抑制剂卡博替尼（cabozantinib，获美国食品药品监督管理局（"Food and Drug Administration, FDA"）批准用于治疗进展性髓样甲状腺癌）与PF-04217903可在纳摩尔浓度下阻断其活性。因此，MET融合激酶可为一类罕见的黑色素瘤亚型提供潜在治疗靶点，而该类亚型目前尚无靶向治疗方案。
加州大学旧金山分校（University of California, San Francisco, UCSF）皮肤病理阵列比较基因组杂交数据库，收录了临床实践中难以分类的肿瘤的拷贝数图谱。该队列中的病例均存在以下两种异常之一：MET基因内部发生拷贝数变异，伴随基因3'端相对拷贝数增加；或7号染色体长臂远端区域出现拷贝数扩增。本队列共纳入6例病例，每例均包含1份重复样本。