Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy
Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy
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DOI：
10.1038/modpathol.2017.127
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发表时间：
2018-03-01
期刊：
影响因子：
7.5
通讯作者：
Harris, Marian H.
中科院分区：
文献类型：
--
作者：
Church, Alanna J.;Calicchio, Monica L.;Harris, Marian H.
婴儿纤维肉瘤和先天性中胚层肾瘤是传统上与 ETV6-NTRK3 基因融合相关的婴儿肿瘤。然而，许多病例报告已经发现这些肿瘤中存在变异融合。为了评估变异 NTRK3 融合的频率，特别是最近发现的 EML4-NTRK3 融合是否会复发，使用 NTRK3 分离 FISH、EML4-NTRK3 双重融合对 63 例婴儿纤维肉瘤、先天性中胚层肾瘤、乳腺类似分泌性癌和分泌性乳腺癌（已知携带复发性 ETV6-NTRK3 融合的肿瘤类型）进行了测试FISH 和靶向 RNA 测序。在两例婴儿纤维肉瘤（其中一例之前已描述过）和一例先天性中胚层肾瘤中发现了 EML4-NTRK3 融合，表明 EML4-NTRK3 融合是这些相关肿瘤中反复发生的遗传事件。与婴儿纤维肉瘤和先天性中胚层肾瘤相关的基因融合范围不断扩大，加上最近出现的针对 NTRK 信号传导抑制的靶向治疗，为 ETV6 断裂部分 FISH 之外的替代检测策略提供了支持。 NTRK3 FISH 或新一代测序的使用将扩大鉴定致癌融合的病例数量，并促进患者的最佳诊断和治疗。
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma ( one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break- part FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.