Cohen Philip R, Kurzrock Razelle
Department of Dermatology, University of California San Diego, San Diego, CA, USA,
Dermatol Ther (Heidelb). 2015 Jun;5(2):129-43. doi: 10.1007/s13555-015-0074-5. Epub 2015 Apr 15.
Merkel cell carcinoma is a neuroendocrine malignancy. Suppressor of fused (SUFU) is a tumor suppressor oncogene that participates in the Hedgehog (Hh) signaling pathway. The aim of the study was to describe a patient whose Merkel cell carcinoma demonstrated a SUFU genomic alteration.
The Hh signaling pathway is involved in the pathogenesis of several tumors, including nevoid basal cell carcinoma syndrome that is associated with an alteration of the patched-1 (PTCH1) gene. Targeted molecular therapy against smoothened (SMO) with vismodegib has been shown to be an effective therapeutic intervention for patients with PTCH-1 mutation. The reported patient was presented with metastatic Merkel cell carcinoma. Analysis of his tumor, using a next-generation sequencing-based assay, demonstrated a genomic aberration of SUFU protein, a component of the Hh signaling pathway that acts downstream to SMO and, therefore, is unlikely to be responsive to vismodegib. Of interest, arsenic trioxide or bromo and extra C-terminal inhibitors impact signals downstream to SUFU, making this aberration conceivably druggable. His tumor has initially been managed with chemotherapy (carboplatin and etoposide) and subsequent radiation therapy is planned.
The pathogenesis of Merkel cell carcinoma is multifactorial, and related to ultraviolet radiation exposure, immunosuppression, and Merkel cell polyomavirus. We report a patient with a mutation in SUFU, a potentially actionable component of the Hh signaling pathway.
默克尔细胞癌是一种神经内分泌恶性肿瘤。融合抑制因子（SUFU）是一种参与刺猬信号通路（Hh）的肿瘤抑制癌基因。本研究的目的是描述一名默克尔细胞癌患者，其肿瘤表现出SUFU基因改变。
Hh信号通路参与多种肿瘤的发病机制，包括与patched-1（PTCH1）基因改变相关的痣样基底细胞癌综合征。已证明使用维莫德吉靶向抑制 smoothened（SMO）对PTCH-1突变患者是一种有效的治疗干预措施。报告的该患者患有转移性默克尔细胞癌。使用基于下一代测序的检测方法对其肿瘤进行分析，结果显示Hh信号通路的一个组成部分SUFU蛋白存在基因组畸变，SUFU在SMO下游发挥作用，因此可能对维莫德吉无反应。有趣的是，三氧化二砷或溴代及额外C末端抑制剂会影响SUFU下游的信号，这使得这种畸变理论上具有可靶向性。他的肿瘤最初采用化疗（卡铂和依托泊苷）治疗，后续计划进行放射治疗。
默克尔细胞癌的发病机制是多因素的，与紫外线辐射暴露、免疫抑制和默克尔细胞多瘤病毒有关。我们报告了一名SUFU发生突变的患者，SUFU是Hh信号通路中一个潜在的可靶向成分。
