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火眼金睛,神兵利器:EWSR1融合基因融合谱的故事

2018-11-06 18:32  阅读(80)  评论(0)  分类:专业

20175月,《Nat Med》杂志发表一篇重量级文章,纪念MSKCC癌症研究中心的科学家采用MSK-IMPACT方法,开展了一项大规模、前瞻性的临床测序研究,他们对1万多名晚期癌症患者,接近300多种肿瘤进行基因二代测序,同时收集这些患者的临床注释、病理等方面的信息,其中EWSR1融合71例,尤文肉瘤占78.37%(29/37),其中25例融合伙伴为FLI13例融合伙伴为ERG1例融合伙伴为ETV4;软组织肉瘤占7.21%(31/430),其中促纤维增生性小圆细胞肿瘤87.50%(21/24)19例融合伙伴为WT11例融合伙伴为RIC3,1例融合伙伴为SLC25A37透明细胞肉瘤占100%(3/3),融合伙伴分别为C11orf49CREB1ATF1;⑶纤维肉瘤占40%(2/5),融合伙伴分别为CREB3L1CREB3L2软骨肉瘤5.71%(2/35),融合伙伴均为NR4A3;⑸软组织肌上皮癌20%(1/5),融合伙伴为ZNF444硬化性上皮样纤维肉瘤占50%(1/2),融合伙伴为CREB3L1未分化多形性肉瘤/性纤维组织细胞瘤1.69%(1/59),融合伙伴为ERG平滑肌肉瘤2.50%(1/40),融合伙伴为AP1B1涎腺癌占42.86%(3/7),黏液表皮样癌,肌上皮癌和其他类型各1例,融合伙伴均为ATF1头颈部肿瘤占1.20%(2/166)1例为牙源性透明细胞癌,融合伙伴为ATF1,另1例为牙源性癌,融合伙伴为FLI1;乳腺癌占0.16% (2/1238),均为浸润性导管癌,融合伙伴为RASL10AMTMR3;非小细胞肺癌占0.06%(1/1563),为肺腺癌,融合伙伴EMID1;膀胱癌占0.25%(1/405),融合伙伴为SLC25A37;前列腺癌占0.16%(1/623),融合伙伴为GAS2L1 [1]

软组织肿瘤分布广、类型多、形态结构复杂多变,且不同类型的软组织形态上相互重叠;近10年由于分子病理学的迅猛发展,EWSR1融合及其融合伙伴的研究逐渐深入,约85%的尤文肉瘤会导致EWSR1-FLI1融合,该融合在尤文肉瘤发生中发挥重要的转录因子作用。尤文肉瘤还有EWSR1其他融合伙伴,包括EWSR1-ERGEWSR1-ETV1EWSR1-ETV4EWSR1-FEVEWSR1-NFATC2EWSR1-POU5F1EWSR1-SMARCA5EWSR1-PATZ1EWSR-SP3EWSR1-ETSEWSR1-ELF5 [2-6]

其他软组织肿瘤也可出现EWSR1融合,包括90%的软组织透明细胞肉瘤中存在EWSR1-ATF1融合,6%的患者中存在EWSR1-CREB1融合;血管瘤样纤维组织细胞瘤:该肿瘤超过90%EWSR1-CREB1融合,少数为EWSR1-ATF1融合;⑶骨外黏液样软骨肉瘤:至少90%的肿瘤具有EWSR1-NR4A3融合,该融合伙伴在其他肉瘤中尚未发现,可作为分子诊断标志,少数肿瘤存在EWSR1-TAF15融合;⑷促结缔组织增生性小圆细胞肿瘤:该肿瘤特征性是EWSR1-WT1融合;软组织肌上皮瘤/肌上皮癌/混合瘤:EWSR1融合在腮腺以外肌上皮性肿瘤中较常见,45%存在EWSR1-POU5F1融合,16%存在EWSR1-PBX1融合,少数肌上皮肿瘤还存在EWSR1-ZNF444融合;⑹黏液脂肪肉瘤:少数存在EWSR1-DDIT3, EWSR1-CHOP融合;⑺胃肠道恶性神经外胚层肿瘤:大多数存在EWSR1-ATF1EWSR1-CREB1融合;⑻硬化性上皮样纤维肉瘤:存在EWSR1-CREB3L1EWSR1-CREB3L3EWSR1-SMAD3 [3, 4, 7, 8 ]

   此外,EWSR1融合也可出现于非软组织肿瘤,包括涎腺癌(EWSR1-ATF1),非小细胞肺癌(EWSR1-EMID1),乳腺癌(EWSR1-RASL10A; EWSR1-MTMR3),膀胱癌(EWSR1-SLC25A37),前列腺癌(EWSR1-GAS2L1),头颈部肿瘤(EWSR1-ATF1; EWSR1-FLI1; EWSR1-KLF15; EWSR1-KLF17; EWSR1-PBX3), 透明细胞癌(EWSR1-CREM),间皮瘤(EWSR1-ATF1; EWSR1-YY1)和骨髓增生性肿瘤(EWSR1-MYB) [9-12]

    正确的诊断是治疗的基础,随着二代测序应用于临床疑难病例的鉴别诊断,越来越多诊断类融合基因被发现,如EWSR1TFE3FUSUSP6HMGA2FOXO1BCORCICDUX4SSX1PAX3等融合基因以及其各种类型的融合伙伴,使得越来越多疑难病例患者得到正确精准的治疗,从而延长总生存时间并获益。因此具有针对性的、全面的二代测序技术有着巨大的前景和临床应用价值,值得重视。

 

 

 

 

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[8] Michal M, Berry R S, Rubin B P, et al. EWSR1-SMAD3-rearranged Fibroblastic Tumor: An Emerging Entity in an Increasingly  More Complex Group of Fibroblastic/Myofibroblastic Neoplasms [J]. Am J Surg Pathol, 2018, 42(10): 1325-1333.

[9] Stevens T M, Qarmali M, Morlote D, et al. Malignant Ewing-Like Neoplasm With an EWSR1-KLF15 Fusion: At the Crossroads of a Myoepithelial Carcinoma and a Ewing-Like Sarcoma. A Case Report With Treatment Options [J]. Int J Surg Pathol, 2018, 26(5): 440-447.

[10] Chapman E, Skalova A, Ptakova N, et al. Molecular Profiling of Hyalinizing Clear Cell Carcinomas Revealed a Subset of Tumors Harboring a Novel EWSR1-CREM Fusion: Report of 3 Cases [J]. Am J Surg Pathol, 2018, 42(9): 1182-1189.

[11] Desmeules P, Joubert P, Zhang L, et al. A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions [J]. Am J Surg Pathol, 2017, 41(7): 980-988.

[12] Pierini T, Di Giacomo D, Pierini V, et al. MYB deregulation from a EWSR1-MYB fusion at leukemic evolution of a JAK2 (V617F) positive primary myelofibrosis [J]. Mol Cytogenet, 2016, 9(1): 68.

 


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