NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma.
NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma.
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DOI：
10.1097/pas.0000000000001055
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发表时间：
2018-06
期刊：
影响因子：
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通讯作者：
Antonescu CR
中科院分区：
文献类型：
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作者：
Chiang S;Cotzia P;Hyman DM;Drilon A;Tap WD;Zhang L;Hechtman JF;Frosina D;Jungbluth AA;Murali R;Park KJ;Soslow RA;Oliva E;Iafrate AJ;Benayed R;Ladanyi M;Antonescu CR
原肌球蛋白受体激酶（Trk）抑制剂在具有NTRK融合的肿瘤患者中显示出高应答率。我们发现了四例NTRK融合蛋白阳性的子宫肉瘤，应与平滑肌肉瘤和未分化子宫肉瘤相鉴别。NTRK重排检测荧光原位杂交（FISH）和/或靶向RNA或DNA测序在四个未分化的子宫肉瘤梭形细胞形态。由于与平滑肌肉瘤的组织学重叠，在97例子宫平滑肌肉瘤中进行了TrkA和pan-Trk免疫组化。用TrkA或pan-Trk染色对肿瘤进行NTRK 1和NTRK 3 FISH。我们还对一例TrkA表达的平滑肌肉瘤进行了全转录组RNA测序，并对另外两例未分化的子宫肉瘤进行了靶向RNA测序。研究组的FISH和/或靶向RNA或DNA测序显示TPM 3-NTRK 1、LMNA-NTRK 1、RBPMS-NTRK 3和TPR-NTRK 1融合。所有肿瘤均由梭形细胞束组成。核分裂指数为7-30个核分裂象/10个高倍视野; 2个肿瘤可见坏死。结蛋白、雌激素受体和孕激素受体在所有肿瘤中均为阴性，而pan-Trk在所有肿瘤中均表达，其中三个肿瘤中同时有TrkA染色。TrkA和/或pan-Trk染色也见于6例平滑肌瘤，但这些肿瘤缺乏NTRK融合或FISH或全转录组测序的替代亚型。在两个未分化的子宫肉瘤中未检测到融合。NTRK融合阳性的子宫梭形细胞肉瘤构成了一种新的肿瘤类型，具有纤维肉瘤的特征;这些肿瘤患者可能受益于Trk抑制。TrkA和pan-Trk在平滑肌瘤中的表达是罕见的，并且与NTRK重排无关。
Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. We identified four NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in four undifferentiated uterine sarcomas with spindle cell morphology. Due to histologic overlap with leiomyosarcoma, TrkA and pan-Trk immunohistochemistry was performed in 97 uterine leiomyosarcomas. NTRK1 and NTRK3 FISH was performed on tumors with TrkA or pan-Trk staining. We also performed whole transcriptome RNA sequencing of a leiomyosarcoma with TrkA expression, and targeted RNA sequencing of two additional undifferentiated uterine sarcomas. FISH and/or targeted RNA or DNA sequencing in the study group showed TPM3-NTRK1, LMNA-NTRK1, RBPMS-NTRK3, and TPR-NTRK1 fusions. All tumors were composed of fascicles of spindle cells. Mitotic index was 7-30 mitotic figures per 10 high power fields; tumor necrosis was seen in two tumors. Desmin, estrogen receptor and progesterone receptor were negative in all tumors, while pan-Trk was expressed in all tumors with concurrent TrkA staining in three of them. TrkA and/or pan-Trk staining was also seen six leiomyosarcomas, but these tumors lacked NTRK fusions or alternative isoforms by FISH or whole transcriptome sequencing. No fusions were detected in two undifferentiated uterine sarcomas. NTRK fusion-positive uterine spindle cell sarcomas constitute a novel tumor type with features of fibrosarcoma; patients with these tumors may benefit from Trk inhibition. TrkA and pan-Trk expression in leiomyosarcomas is rare and does not correlate with NTRK rearrangement.