Diagnosis of NUT Midline Carcinoma Using a NUT-specific Monoclonal Antibody
Diagnosis of NUT Midline Carcinoma Using a NUT-specific Monoclonal Antibody
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DOI：
10.1097/pas.0b013e318198d666
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发表时间：
2009-07-01
影响因子：
5.6
通讯作者：
French, Christopher A.
中科院分区：
文献类型：
--
作者：
Haack, Herbert;Johnson, Laura A.;French, Christopher A.
NUT 中线癌 (NMC) 是一种均致死性恶性肿瘤，其定义为染色体 15q14 上睾丸核蛋白 (NUT) 基因的重排。 NMC 在形态学上与其他低分化癌无法区分，目前通常通过荧光原位杂交（FISH）进行诊断。由于正常 NUT 表达仅限于睾丸和卵巢，我们推断 NUT 的免疫组织化学 (IHC) 染色将有助于诊断 NMC。为此，我们针对重组 NUT 多肽制备了高度特异性的兔单克隆抗体 C52，并开发了 IHC 染色方案。 C52 染色的敏感性和特异性在一组 1068 个组织中进行了评估，这些组织主要是不同类型的癌症 (n = 906)，包括 30 个 NMC。 NUT 重排的分离 FISH 被用作 NMC 的“金标准”诊断测试。癌症中的 C52 免疫反应性仅限于 NMC。 IHC 染色的敏感性为 87%，特异性为 100%，阴性预测值为 99%，阳性预测值为 100%。 C52 IHC 检测到两例新的含有 BRD4-NUT 融合的 NMC 病例。但被传统的 FISH 遗漏了。在这两种情况下，这些肿瘤都含有隐秘的 BRD4-NUT 重排，正如使用一组精细探针进行 FISH 证实的那样。一些生殖细胞肿瘤，包括 64% 的无性细胞瘤，表现出较弱的 NUT 免疫反应性，与正常生殖细胞中 NUT 的表达一致。我们得出的结论是，使用 C52 单克隆抗体进行 IHC 染色是一种高度敏感和特异的测试，可以可靠地区分 NMC 与其他形式的癌症。 NUT 抗体正在准备商业发布，并将在不久的将来上市。
NUT midline carcinoma (NMC) is a uniformly lethal malignancy that is defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14. NMCs are morphologically indistinguishable from other poorly differentiated carcinomas, and the diagnosis is usually made currently by fluorescence in situ hybridization (FISH). As normal NUT expression is confined to testis and ovary, we reasoned that an immunohistochemical (IHC) stain for NUT would be useful in diagnosing NMC. To this end, we raised a highly specific rabbit monoclonal antibody, C52, against a recombinant NUT polypeptide, and developed an IHC staining protocol. The sensitivity and specificity of C52 staining was evaluated in a panel of 1068 tissues, predominantly diverse types of carcinomas (n = 906), including 30 NMCs. Split-apart FISH for NUT rearrangement was used as a "gold standard" diagnostic test for NMC. C52 immunoreactivity among carcinomas was confined to NMCs. IHC staining had a sensitivity of 87%, a specificity of 100%, a negative predictive value of 99%, and a positive predictive value of 100%. Two new cases of NMC containing BRD4-NUT fusions were detected by C52 IHC. but missed by conventional FISH. In both instances, these tumors contained cryptic BRD4-NUT rearrangements, as confirmed by FISH using a refined set of probes. Some germ cell tumors, including 64% of dysgerminomas, showed weak NUT immunoreactivity, consistent with the expression of NUT in normal germ cells. We conclude that IHC staining with the C52 monoclonal antibody is a highly sensitive and specific test that reliably distinguishes NMC from other forms of carcinoma. The NUT antibody is being prepared for commercial release and will be available in the near future.