A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation
A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation
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DOI：
10.1038/s41379-019-0323-8
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发表时间：
2020-03-01
期刊：
影响因子：
7.5
通讯作者：
Tirode, Franck
中科院分区：
文献类型：
--
作者：
Le Loarer, Francois;Cleven, Arjen H. G.;Tirode, Franck
TFCP 2融合的横纹肌肉瘤代表了一种新出现的肿瘤亚型，最初通过RNA测序发现。我们在此报告的临床病理学，转录和基因组特征的一系列14例。回顾性和前瞻性招募病例，并进行免疫组化研究（MYF 4、MYOD 1、S100、AE 1/E3、ALK），TFCP 2断裂探针荧光原位杂交（n = 10/14），阵列比较基因组杂交（Agilent），全RNA测序（Truseq Exome，Illumina）或基于锚定多重PCR的靶向下一代测序（Archer（R）Fusionnucleotide（R）Sarcoma试剂盒）。患者年龄范围为11 - 86岁，包括5例儿科病例。肿瘤位于骨（n = 12/14）和软组织（n = 2/14）。大多数骨肿瘤侵犯周围软组织。颅面骨过度代表（n = 8/12）。中位生存期为8个月，5名患者目前存活，中位随访时间为20个月。大多数肿瘤表现为梭形细胞和上皮样细胞混合型，细胞核多为泡状。所有肿瘤均表达角蛋白，并显示横纹肌原表型（定义为MYF 4和/或MYOD 1的表达）。除3例病例外，所有病例均过表达ALK，在分离FISH（n = 5）和下一代测序（n = 14）上均无潜在ALK融合。ALK上调通常与基因组水平的内部缺失相关。TFCP 2与EWSR 1（n = 6）或FUS（n = 8）的5 '端融合。EWSR 1在两例软组织病例中均受累。TFCP 2断裂探针FISH检测8例均为阳性，其中1例信号不平衡。在阵列CGH上，所有测试的肿瘤显示复杂的遗传谱，基因组指数范围从13到107.55，并且复发性CDKN 2A缺失。FET-TFCP 2横纹肌肉瘤聚集在一起，与其他横纹肌肉瘤亚组不同。总之，我们的数据证实并扩大了新的FET-TFCP 2横纹肌肉瘤家族的谱，该家族与颅面骨的偏好、侵袭性病程和复发性病理特征相关。它们与ALK过表达的相关性可能代表了治疗的脆弱性。
Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer (R) FusionPlex (R) Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5 ' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.