Departments of *Pathology, †Surgery, ‡Medicine, and §Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
J Thorac Oncol. 2015 Feb;10(2):373-80. doi: 10.1097/JTO.0000000000000397.
The characterization of the molecular alterations in thymic epithelial tumors may lead to a better understanding of tumorigenesis, new therapeutic targets, and biomarkers in these tumors.
Paired tissue (tumor and matched normal) from 15 thymic carcinomas (TCA) and six B3 thymomas were evaluated by exon capture of 275 cancer-related genes, followed by deep coverage next-generation sequencing, which identifies somatic sequence variants, small insertions and deletions, and copy number alterations involving all exons of the captured genes.
Non-silent somatic mutations were identified in 12 of 15 (80%) TCA with a median of one mutation per tumor (range 0-26). Recurrent mutations were identified in tumor suppressor genes TP53 (n = 4), SMAD4 (n = 2), and CYLD (n = 2); and chromatin remodeling genes KDM6A (n = 3), SETD2 (n = 2), MLL3 (n = 2), and MLL2 (n = 2). Tumors with TP53 mutation appeared to exhibit more aggressive behavior. Therefore, the role of P53 was evaluated by immunohistochemistry in an additional ten cases. P53 overexpression correlated with TP53 mutation. These tumors had a higher rate of recurrence and death of disease compared to carcinoma with normal p53 expression (p = 0.02 for disease-free survival and p = 0.05 for overall survival). Among the B3 thymomas, mutations were identified in four of six tumors. Mutations in BCOR (BCL6 co-repressor) were seen in three thymomas and MLL3 (involved in histone methylation) in one tumor.
Next-generation sequencing of cancer genes in thymic epithelial tumors revealed a low frequency of mutation, with different patterns between TCA and B3 thymomas. TP53 and BCOR were the most frequently mutated genes in TCA and B3 thymomas, respectively. Alterations in p53 are associated with worse prognosis in TCA.
胸腺上皮肿瘤的分子改变特征可能有助于更好地了解肿瘤发生机制、新的治疗靶点和这些肿瘤的生物标志物。
对 15 例胸腺癌（TCA）和 6 例 B3 胸腺瘤的配对组织（肿瘤和匹配的正常组织）进行 275 个癌症相关基因的外显子捕获，然后进行深度覆盖下一代测序，该测序可识别涉及捕获基因所有外显子的体细胞序列变异、小插入和缺失以及拷贝数改变。
15 例 TCA 中有 12 例（80%）发现非沉默性体细胞突变，每个肿瘤平均有一个突变（范围 0-26）。在肿瘤抑制基因 TP53（n = 4）、SMAD4（n = 2）和 CYLD（n = 2）中发现了复发性突变；以及染色质重塑基因 KDM6A（n = 3）、SETD2（n = 2）、MLL3（n = 2）和 MLL2（n = 2）。TP53 突变的肿瘤似乎表现出更具侵袭性的行为。因此，在另外 10 例病例中通过免疫组织化学评估了 P53 的作用。P53 过表达与 TP53 突变相关。与 P53 表达正常的癌相比，这些肿瘤的复发率和疾病死亡率更高（无病生存率 p = 0.02，总生存率 p = 0.05）。在 B3 胸腺瘤中，6 例中有 4 例发现突变。在 3 例胸腺瘤中发现了 BCOR（BCL6 共抑制因子）突变，在 1 例肿瘤中发现了 MLL3（参与组蛋白甲基化）突变。
在胸腺上皮肿瘤的癌症基因的下一代测序中，突变频率较低，TCA 和 B3 胸腺瘤之间的模式不同。TP53 和 BCOR 分别是 TCA 和 B3 胸腺瘤中最常突变的基因。p53 的改变与 TCA 的预后较差相关。
