Chu Ying-Hsia, Sadow Peter M
Fellow, Molecular Genetic Pathology, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Director, Head & Neck Pathology, Massachusetts General Hospital and Associate Professor of Pathology, Harvard Medical School, Departments of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Diagn Histopathol (Oxf). 2021 Jun;27(6):252-262. doi: 10.1016/j.mpdhp.2021.03.003. Epub 2021 Mar 31.
Activating genomic alterations in protein kinases represent a major driving force in thyroid carcinogenesis. Recently, oncogenic kinase fusions have been a central subject of pharmaceutical development, with a rapidly growing number of inhibitors validated for treating molecularly matched malignancies. Thyroid carcinomas harbor actionable kinase fusions in 10-15% of cases, occupying an increasingly recognized subpopulation of thyroid carcinomas with enhanced attention to molecular profiling. With advances in kinase-based cancer therapy, several challenges have emerged for pathologists. To interrogate an expanding list of targetable genes, the diagnostic paradigm has shifted from conventional single-gene methods toward high-throughput nucleic acid sequencing. Considering the relatively low incidence of most kinase fusions, a selective approach for molecular testing that utilizes histologic and immunohistochemical findings in triaging cases becomes essential for laboratory resource management. Moreover, kinase inhibitor resistance inevitably evolves, requiring a multimodal approach to optimal therapy, despite targeted therapies showing an enhanced, durable response. In this review, we assess the current clinicopathologic understanding and ongoing investigational topics in kinase fusion-related thyroid carcinomas.
蛋白激酶中的激活基因组改变是甲状腺癌发生的主要驱动力。最近，致癌激酶融合一直是药物研发的核心主题，越来越多的抑制剂被证实可用于治疗分子匹配的恶性肿瘤。甲状腺癌在10%至15%的病例中存在可靶向的激酶融合，这一甲状腺癌亚群日益受到认可，对分子谱分析的关注度也不断提高。随着基于激酶的癌症治疗的进展，病理学家面临着几个挑战。为了检测越来越多的可靶向基因，诊断模式已从传统的单基因方法转向高通量核酸测序。考虑到大多数激酶融合的发生率相对较低，一种利用组织学和免疫组化结果对病例进行分类的分子检测选择性方法对于实验室资源管理至关重要。此外，激酶抑制剂耐药性不可避免地会出现，尽管靶向治疗显示出增强的持久反应，但仍需要采用多模式方法进行最佳治疗。在本综述中，我们评估了目前对激酶融合相关甲状腺癌的临床病理认识以及正在进行的研究课题。
