肿瘤细胞需要激活端粒维持机制，实现无限复制。大部分证据支持肉瘤主要使用替代端粒长度调节（ALT）机制，常伴随ATRX和DAXX的改变。在我们的数据集中，只有12.3%的肉瘤携带这些基因的变异。因此，我们检查了肉瘤中高端粒含量的其他基因决定因素的存在。我们的数据集包括13555个肉瘤样本，作为基金会一血病平台的例行临床护理的一部分进行测序。我们观察到所有样本中的媒体端粒含量为每个GC匹配百万个读数的622.3个端粒读数（TRPM）。与先前的研究一致，ATRX和POT1改变的肉瘤的端粒含量显著较高。我们进一步观察到，在RAD51B或GID4改变的肉瘤中，存在高端粒含量的样本富集，尤其是在子宫平滑肌肉瘤中的RAD51B改变和软组织肉瘤（未明确指定，nos）中的GID4改变。此外，RAD51B和POT1的改变与ATRX和DAXX的改变互斥，暗示它们功能上的冗余性。我们的结果提示了RAD51B和GID4在肉瘤中端粒伸长中的作用，并为致力于靶向肿瘤发生的这一关键途径的药物提供了研究机会。© 2023年。Springer Nature 有限公司和阿卜杜勒阿齐兹大学基因医学研究卓越中心。

Tumor cells need to activate a telomere maintenance mechanism, enabling limitless replication. The bulk of evidence supports that sarcomas predominantly use alternative lengthening of telomeres (ALT) mechanism, commonly associated with alterations in ATRX and DAXX. In our dataset, only 12.3% of sarcomas harbored alterations in these genes. Thus, we checked for the presence of other genomic determinants of high telomeric content in sarcomas. Our dataset consisted of 13555 sarcoma samples, sequenced as a part of routine clinical care on the FoundationOne®Heme platform. We observed a median telomeric content of 622.3 telomeric reads per GC-matched million reads (TRPM) across all samples. In agreement with previous studies, telomeric content was significantly higher in ATRX altered and POT1 altered sarcomas. We further observed that sarcomas with alterations in RAD51B or GID4 were enriched in samples with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B and soft tissue sarcoma (not otherwise specified, nos) for GID4, Furthermore, RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of functional redundancy. Our results propose a role played by RAD51B and GID4 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this critical pathway in tumorigenesis.© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.