转座子衍生的转录本在 RNA 序列中含量丰富，但它们的结构和功能，特别是来自未注释或体细胞获得的转座子的融合转录本，仍然尚未得到充分研究。在这里，我们开发了一种新的生物信息学工具来检测 RNA 测序数据中的转座子融合转录本，并对 34 种癌症类型的 10,257 个癌症样本以及 3,088 个正常组织样本进行了泛癌分析。我们鉴定了 52,277 个癌症特异性融合，每个癌症有约 30 个事件，以及转座子内易形成融合的热点位点。内含子转座子的外显子化是最常见的基因融合，而体细胞 L1 插入构成癌症特异性融合的一小部分。来源 L1 和 HERV（而非 Alus）在融合形成后在癌症中显示出 DNA 甲基化降低。总体而言，癌症特异性 L1 融合富含肿瘤抑制基因，而 Alu 融合富含癌基因，包括预测患者生存的 EZH2 中反复出现的 Alu 融合。我们还证明转座子衍生肽触发 CD8 T 细胞激活的程度与 EBV 病毒相当。我们的研究结果揭示了不同家族的转座子融合背后不同的表观遗传和致瘤机制，并强调转座子作为新的治疗靶点和有效新抗原的来源。

Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with ∼30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens.