Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions.
Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions.
复制标题
DOI：
10.1097/pas.0000000000000911
复制
发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Jungbluth AA
中科院分区：
文献类型：
--
作者：
Hechtman JF;Benayed R;Hyman DM;Drilon A;Zehir A;Frosina D;Arcila ME;Dogan S;Klimstra DS;Ladanyi M;Jungbluth AA
通常通过基于核酸的测定检测的活化神经营养性酪氨酸受体激酶（NTRK）融合物是高度可靶向的并且定义某些肿瘤。在这里，我们探讨泛TRK免疫组织化学（IHC）检测NTRK融合的效用。使用基于DNA的下一代测序测定法MSK-IMPACT前瞻性地检测NTRK重排。通过Archer Dx融合测定评估新NTRK重排转录成潜在功能性融合转录物。使用mAb EPR 17341对所有NTRK重排病例和20例Archer NTRK融合阴性病例进行Pan-Trk IHC检测。在23例NTRK重排病例中，15例已知存在激活融合。Archer在8种功能意义不确定的新型NTRK重排中的6种中检测到融合转录本。在21例经Archer证实的NTRK融合转录本中，20例Pan-Trk IHC阳性。不一致的阴性病例是ETV 6-NTRK 3融合的错配修复缺陷型结直肠癌。所有20例额外的Archer阴性病例具有一致的泛TRK IHC结果。转录NTRK融合的Pan-Trk IHC灵敏度和特异性分别为95.2%和100%。所有阳性IHC病例均具有细胞质染色，同时发现以下融合伴侣特异性模式：所有5个LMNA-NTRK 1融合体均显示核膜加重，所有4个TPM 3/4融合体均显示细胞膜加重，一半（3/6）ETV 6-NTRK 3融合体显示核染色。Pan-Trk IHC是NTRK融合的时间和组织有效的筛选，特别是在驱动程序阴性的晚期恶性肿瘤和分泌性癌和先天性纤维肉瘤的潜在病例中。Pan-Trk IHC可以帮助确定新NTRK重排是否发生翻译。
Activating neurotrophic tyrosine receptor kinase (NTRK) fusions, typically detected via nucleic acid based assays, are highly targetable and define certain tumors. Here, we explore the utility of pan-TRK immunohistochemistry (IHC) to detect NTRK fusions. NTRK rearrangements were detected prospectively using MSK-IMPACT, a DNA-based next generation sequencing assay. Transcription of novel NTRK rearrangements into potentially functional fusion transcripts was assessed via Archer Dx fusion assay. Pan-Trk IHC testing with mAb EPR17341 was performed on all NTRK rearranged cases and 20 cases negative for NTRK fusions on Archer. Of 23 cases with NTRK rearrangements, 15 had known activating fusions. Archer detected fusion transcripts in 6 of 8 novel NTRK rearrangements of uncertain functional significance. Pan-Trk IHC was positive in 20 of 21 cases with NTRK fusion transcripts confirmed by Archer. The discordant negative case was a mismatch repair-deficient colorectal carcinoma with an ETV6-NTRK3 fusion. All 20 additional Archer-negative cases had concordant pan-TRK IHC results. Pan-Trk IHC sensitivity and specificity for transcribed NTRK fusions was 95.2% and 100%, respectively. All positive IHC cases had cytoplasmic staining while the following fusion partner-specific patterns were discovered: all 5 LMNA-NTRK1 fusions displayed nuclear membrane accentuation, all 4 TPM3/4 fusions displayed cellular membrane accentuation, and half (3/6) of ETV6-NTRK3 fusions displayed nuclear staining. Pan-Trk IHC is a time- and tissue-efficient screen for NTRK fusions, particularly in driver-negative advanced malignancies and potential cases of secretory carcinoma and congenital fibrosarcoma. Pan-Trk IHC can help determine whether translation occurs for novel NTRK rearrangements.