Brown Lauren M, Tax Gabor, Acera Mateos Pablo, de Weck Antoine, Foresto Steve, Robertson Thomas, Jalud Fatimah, Ajuyah Pamela, Barahona Paulette, Mao Jie, Dolman M Emmy M, Wong Marie, Mayoh Chelsea, Cowley Mark J, Lau Loretta M S, Sadras Teresa, Ekert Paul G
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
NPJ Precis Oncol. 2025 May 10;9(1):137. doi: 10.1038/s41698-025-00928-3.
Precision medicine programs like the Zero Childhood Cancer Program perform comprehensive molecular analysis of patient tumors, enabling detection of novel structural variants that may be cryptic to standard techniques. Identification of these variants can impact individual patient treatment, and beyond this establish new mechanisms of oncogenic activation. We have identified a novel internal tandem duplication (ITD) in the receptor tyrosine kinase (RTK), NTRK2, in a patient with FOXR2-activated CNS neuroblastoma. The ITD spans exons 10-13 of NTRK2 encoding the transmembrane domain. NTRK2 ITD is transforming and sensitive to TRK inhibition. In silico structural predictions suggested the duplication of an alpha-helix region and juxtaposed tyrosine residues that play a role in facilitating autophosphorylation. Consistent with this, mutation of these residues inhibited cellular transformation. This is the first report of an ITD spanning the transmembrane domain of an RTK, characterizing an additional mechanism by which RTKs are activated in cancer.
像“零儿童癌症计划”这样的精准医疗项目会对患者肿瘤进行全面的分子分析，从而能够检测出一些标准技术可能难以发现的新型结构变异。识别这些变异会影响个体患者的治疗，除此之外，还能建立致癌激活的新机制。我们在一名患有FOXR2激活型中枢神经系统神经母细胞瘤的患者中，在受体酪氨酸激酶（RTK）NTRK2中发现了一种新型的内部串联重复（ITD）。该ITD跨越了编码跨膜结构域的NTRK2的第10至13外显子。NTRK2 ITD具有转化能力且对TRK抑制敏感。计算机模拟结构预测表明，一个α螺旋区域以及并列的酪氨酸残基发生了重复，这些在促进自身磷酸化过程中发挥作用。与此一致的是，这些残基的突变抑制了细胞转化。这是关于RTK跨膜结构域存在ITD的首篇报道，描述了RTK在癌症中被激活的另一种机制。
