Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
Oncogene. 2011 Oct 13;30(41):4243-60. doi: 10.1038/onc.2011.133. Epub 2011 May 9.
Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin. Immunohistochemical analysis of a tumour microarray showed strong membranous TRKB and TRKC staining in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 expression. Membranous TRKC overexpression was also observed in 70% of sporadic BCCs. RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours. These results suggest that TRK inhibition could be used as a strategy to treat tumours with loss of functional CYLD.
携带肿瘤抑制基因 CYLD 种系突变的个体患破坏性皮肤附属器肿瘤的风险很高，其特征性肿瘤是高度组织化的圆柱瘤。在此，我们通过阵列比较基因组杂交和基因表达微阵列分析来分析 CYLD 突变肿瘤基因组。除了 CYLD 基因所在的染色体 16q 的杂合性缺失（LOH）外，CYLD 突变肿瘤的基因组没有拷贝数异常。与周围正常皮肤相比，CYLD 突变肿瘤的基因表达谱显示出原肌球蛋白激酶（TRK）信号的失调，TRKB 和 TRKC 的表达上调。肿瘤微阵列的免疫组织化学分析显示，圆柱瘤中存在强烈的膜 TRKB 和 TRKC 染色，以及 ERK 磷酸化和 BCL2 表达水平升高。在 70%的散发性基底细胞癌中也观察到膜 TRKC 过表达。TRKB 和 TRKC 的 RNA 干扰介导的沉默，以及使用小分子 TRK 抑制剂 lestaurtinib 治疗，减少了从 CYLD 突变肿瘤建立的 3D 原代细胞培养物中的集落形成和增殖。这些结果表明，TRK 抑制可作为治疗功能性 CYLD 缺失肿瘤的一种策略。
