Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing
Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing
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DOI：
10.1016/j.cllc.2020.11.010
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发表时间：
2021-03-19
影响因子：
3.6
通讯作者：
Inagaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Sakane, Tadashi;Sakamoto, Yuma;Inagaki, Hiroshi
胸腺癌的突变谱仍不清楚。我们使用新一代测序面板分析了 54 例胸腺癌，其中包括 44 例鳞状细胞癌。 3 个最常见突变的基因是 TP53 (18.5%)、KIT (7.4%) 和 PDGFRA (5.6%)。受体酪氨酸激酶基因突变的胸腺鳞状细胞癌的总生存时间明显短于没有突变的胸腺鳞状细胞癌（P [0.0481）。背景：胸腺癌是一种罕见的纵隔肿瘤，对其遗传变异性知之甚少，这阻碍了靶向治疗的发展。患者和方法：我们在 48 例胸腺癌和 6 例胸腺神经内分泌肿瘤中测试了包含 50 个常见癌症相关基因的下一代测序面板。结果：我们在 54 个病例中的 21 个病例中检测到 42 个变异。胸腺癌和胸腺神经内分泌肿瘤的突变频率无显着差异。其中，TP53是最常见的突变基因（18.5%），其次是KIT（7.4%）和PDGFRA（5.6%）。根据基因通路和基因组，p53通路（包括TP53和ATM）最常受到影响（20.4%），其次是受体酪氨酸激酶（RTK）/RAS通路（18.5%）和PI3K通路（5.6%）。根据专家指导的精准肿瘤学知识库 OncoKB，10 例病例（18.5%）中有 7 个基因被注释为 1 级证据，提示了潜在的治疗靶点。对胸腺鳞状细胞癌进行的预后分析显示，RTK 基因突变的肿瘤病例，包括 KIT (7.4%)、PDGFRA (5.6%) 和 EGFR (3.7%)，与较差的总生存时间显着相关 (P = .0481)。在临床病理因素中，Masaoka 分期晚期与较差的总生存率略有相关 (P = .0757)。在随后的多变量分析中，这两个因素均未达到统计显着性。结论：在这项初步的下一代测序研究中，我们意外地发现了证据表明一些基因突变可能是治疗靶点。 RTKs基因突变可能是胸腺鳞状细胞癌有价值的预后因素。胸腺癌的突变谱仍不清楚。我们使用新一代测序面板分析了 54 例胸腺癌，其中包括 44 例鳞状细胞癌。 3 个最常见突变的基因是 TP53 (18.5%)、KIT (7.4%) 和 PDGFRA (5.6%)。受体酪氨酸激酶基因突变的胸腺鳞状细胞癌的总生存时间明显短于没有突变的胸腺鳞状细胞癌（P [0.0481）。背景：胸腺癌是一种罕见的纵隔肿瘤，对其遗传变异性知之甚少，这阻碍了靶向治疗的发展。患者和方法：我们在 48 例胸腺癌和 6 例胸腺神经内分泌肿瘤中测试了包含 50 个常见癌症相关基因的下一代测序面板。结果：我们在 54 个病例中的 21 个病例中检测到 42 个变异。胸腺癌和胸腺神经内分泌肿瘤的突变频率无显着差异。其中，TP53是最常见的突变基因（18.5%），其次是KIT（7.4%）和PDGFRA（5.6%）。根据基因通路和基因组，p53通路（包括TP53和ATM）最常受到影响（20.4%），其次是受体酪氨酸激酶（RTK）/RAS通路（18.5%）和PI3K通路（5.6%）。根据专家指导的精准肿瘤学知识库 OncoKB，10 例病例（18.5%）中有 7 个基因被注释为 1 级证据，提示了潜在的治疗靶点。对胸腺鳞状细胞癌进行的预后分析显示，RTK 基因突变的肿瘤病例，包括 KIT (7.4%)、PDGFRA (5.6%) 和 EGFR (3.7%)，与较差的总生存时间显着相关 (P = .0481)。在临床病理因素中，Masaoka 分期晚期与较差的总生存率略有相关 (P = .0757)。在随后的多变量分析中，这两个因素均未达到统计显着性。结论：在这项初步的下一代测序研究中，我们意外地发现了证据表明一些基因突变可能是治疗靶点。 RTKs基因突变可能是胸腺鳞状细胞癌的一个有价值的预后因素
The mutational profile of thymic carcinoma still remains unclear. We analyzed 54 thymic carcinomas, including 44 squamous cell carcinomas, using a next-generation sequencing panel. The 3 most frequently mutated genes were TP53 (18.5%), KIT (7.4%), and PDGFRA (5.6%). The thymic squamous cell carcinomas with gene mutations in receptor tyrosine kinases exhibited significantly shorter overall survival time than those without (P [ .0481). Background: Thymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. Patients and Methods: We tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. Results: We detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. Conclusions: In this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous cell carcinoma.The mutational profile of thymic carcinoma still remains unclear. We analyzed 54 thymic carcinomas, including 44 squamous cell carcinomas, using a next-generation sequencing panel. The 3 most frequently mutated genes were TP53 (18.5%), KIT (7.4%), and PDGFRA (5.6%). The thymic squamous cell carcinomas with gene mutations in receptor tyrosine kinases exhibited significantly shorter overall survival time than those without (P [ .0481). Background: Thymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. Patients and Methods: We tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. Results: We detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. Conclusions: In this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous