Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen‐related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. Methods: We used mate‐pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. Results: We observed that inter‐ or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement‐related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient‐specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic‐like events negatively impact survival. Conclusions: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

中文翻译：

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间皮瘤中复杂染色体重排的新抗原潜力

简介：恶性胸膜间皮瘤是一种主要与接触致癌物石棉有关的疾病。其他致癌物相关肿瘤与高肿瘤突变负荷相关，而间皮瘤则不然。我们试图解决这种差异。方法：我们使用配对 (n = 22)、RNA (n = 28) 和 T 细胞受体测序以及计算机预测和免疫学分析来了解染色体的结构变异如何影响转录组。结果：我们观察到每个样本中都存在染色体间或染色体内的重排，并且经常以染色体发生的模式出现，例如染色体合并或染色体碎裂。预测重排相关连接的转录会导致许多潜在的新抗原，其中一些被证明可以结合患者特异性主要组织相容性复合物分子并扩大瘤内 T 细胞克隆。对这些预测的新抗原有反应的 T 细胞也存在于患者的循环 T 细胞库中。对癌症基因组图谱中间皮瘤队列的基因组阵列数据的分析表明，多个染色体碎裂样事件对生存率产生负面影响。结论：我们的发现代表了由结构染色体重排驱动的潜在新抗原表达的发现。这些结果可能对开发新的免疫治疗策略和选择接受免疫治疗的患者有影响。s 循环 T 细胞库。对癌症基因组图谱中间皮瘤队列的基因组阵列数据的分析表明，多个染色体碎裂样事件对生存率产生负面影响。结论：我们的发现代表了由结构染色体重排驱动的潜在新抗原表达的发现。这些结果可能对开发新的免疫治疗策略和选择接受免疫治疗的患者有影响。s 循环 T 细胞库。对癌症基因组图谱中间皮瘤队列的基因组阵列数据的分析表明，多个染色体碎裂样事件对生存率产生负面影响。结论：我们的发现代表了由结构染色体重排驱动的潜在新抗原表达的发现。这些结果可能对开发新的免疫治疗策略和选择接受免疫治疗的患者有影响。