Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Cancer Genet. 2021 Nov;258-259:110-119. doi: 10.1016/j.cancergen.2021.10.005. Epub 2021 Oct 18.
The NTRK gene family is composed of NTRK1, NTRK2, and NTRK3, which encode three tropomyosin-receptor kinases, belonging to a class of tyrosine kinase receptors. These proteins are known to play roles in cell proliferation, differentiation, apoptosis, and survival. Fusions involving the NTRK genes are long known as drivers in many tumors. Although they occur in less than 5% of all malignancies, their occurrence in a great diversity of tumors has been documented. Several rare tumors including infantile fibrosarcoma, secretory breast carcinoma, and mammary analogue secretory carcinoma are accompanied by NTRK fusions in more than 90% of cases, demonstrating a diagnostic value for the NTRK fusion testing in these tumors. More recently, the development of effective targeted therapies has created a demand for their detection in all malignancies. A variety of approaches are available for testing including immunohistochemistry, fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and DNA- and RNA-based next-generation sequencing (NGS). This article reviews the molecular biology and tumorigenesis of NTRK fusions, their prevalence and clinical significance with a focus on available methods for fusion detection. The advantages and limitations of different technologies, the best practice algorithms for NTRK fusion detection, and the future direction of NTRK testing are also discussed.
NTRK 基因家族由 NTRK1、NTRK2 和 NTRK3 组成，它们分别编码三种原肌球蛋白受体激酶，属于酪氨酸激酶受体家族。这些蛋白被认为在细胞增殖、分化、凋亡和存活中发挥作用。涉及 NTRK 基因的融合长期以来被认为是许多肿瘤的驱动因素。尽管它们发生在不到所有恶性肿瘤的 5%中，但它们在多种肿瘤中的发生已被记录在案。一些罕见的肿瘤，包括婴儿纤维肉瘤、分泌性乳腺癌和乳腺类似分泌癌，在超过 90%的病例中伴有 NTRK 融合，这证明了在这些肿瘤中进行 NTRK 融合检测具有诊断价值。最近，有效的靶向治疗药物的开发，对所有恶性肿瘤中检测 NTRK 融合的需求也在不断增加。目前有多种方法可用于检测，包括免疫组织化学、荧光原位杂交（FISH）、逆转录聚合酶链反应（RT-PCR）以及基于 DNA 和 RNA 的下一代测序（NGS）。本文综述了 NTRK 融合的分子生物学和肿瘤发生机制，及其在所有恶性肿瘤中的流行程度和临床意义，重点介绍了融合检测的方法。还讨论了不同技术的优缺点、NTRK 融合检测的最佳实践算法以及 NTRK 检测的未来方向。
