Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

中文翻译：

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内源性逆转录病毒转录水平与多种转移性癌症类型的免疫原性特征相关

实体肿瘤的下一代测序揭示了肿瘤免疫原性的可变特征，但驱动这种变异的潜在分子特征尚未完全了解。尽管内源性逆转录病毒 (ERV) 转录物的表达可以在某些癌症模型中提供肿瘤特异性新抗原的来源，但 ERV 水平与不同类型转移性癌症的免疫原性之间的关联尚未完全确定。我们对 199 名转移性乳腺癌、结肠直肠癌和胰腺导管腺癌患者的整合队列的基因组、转录组和临床数据进行了生物信息学分析。在每种癌症类型中，我们确定了一个病毒拟态肿瘤亚组，其中 ERV 水平增加与自主抗病毒反应和免疫原性的转录特征相结合。此外，病毒模拟结直肠和胰腺肿瘤显示 DNA 去甲基化基因 TET2 的表达增加。总之，这些数据表明在三种不同的转移性癌症类型中存在 ERV 相关病毒模拟表型，同时表明 ERV 丰度、表观遗传失调和免疫原性之间存在联系。