PO.CL11.01 · 临床研究
蒽环类药物对肿瘤、血液和心脏基因组晚期效应背后的突变图谱
The mutational landscape underlying the late effects of anthracyclines on tumor, blood, and heart genomes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
动机：蒽环类药物作为一种必不可少的化疗药物，对癌症幸存者的多种晚期效应负担有着不成比例的贡献，包括癌症复发、治疗相关性血液肿瘤以及致死性心脏毒性。尽管临床使用已有数十年，这些晚期效应背后的机制——尤其是蒽环类药物如何损伤肿瘤性和非肿瘤性组织（血液和心脏）的基因组——仍然知之甚少。更深入地理解蒽环类药物在组织特异性层面的突变结局，或可产生有前景的生物标志物，从而改善癌症幸存者的生存照护。
方法：我们组建了一个由未经治疗或经蒽环类药物治疗的肿瘤、血液和心脏样本构成的队列。肿瘤和血液样本来自纳入SickKids癌症测序项目的儿童癌症患者。心脏样本取自接受蒽环类药物治疗后发生严重心脏毒性并需要心脏移植的癌症幸存者。我们对每种组织类型的DNA进行了测序，以鉴定蒽环类药物诱导的体细胞突变。
结果：我们的初步结果显示，在所有组织类型中，经蒽环类药物治疗与未治疗样本之间的全基因组突变差异极小。我们推测蒽环类药物可能在独特的基因组拓扑结构中引起局部突变。事实上，我们发现经蒽环类药物治疗的组织在其各自起源细胞的开放染色质中呈现体细胞突变的强烈富集，但因突变类型不同而有差异。经蒽环类药物治疗的肿瘤在启动子和内含子中呈现单核苷酸变异富集，而在外显子区域缺失突变减少。然而，利用这些癌症患者匹配的血液样本表明，经蒽环类药物治疗的血液样本在多种血细胞类型的开放染色质中呈现缺失突变富集。尽管心脏不具备增殖能力，经蒽环类药物治疗的心脏在胎儿心肌细胞开放染色质和非B型DNA区域仍呈现插入-缺失突变的显著富集。最后，通过对蒽环类药物暴露的心脏、肿瘤和血液样本体细胞突变谱的比较分析，我们揭示了此前未被充分认识的组织特异性突变特征。
意义：本研究首次刻画了蒽环类药物对肿瘤、血液和心脏的组织特异性基因组后果。对高危患者的早期识别将变革生存照护，确保癌症患儿不只是从诊断中存活下来——而是在其后蓬勃成长。
查看英文原文 English abstract
Motivation : Anthracyclines, an essential chemotherapy, disproportionately contributes to several late effects burdening survivors of cancer, including cancer relapse, therapy-related blood cancers, and fatal cardiotoxicity. Despite decades of clinical use, the mechanisms underlying these late effects - particularly how anthracyclines damage the genome of neoplastic and non-neoplastic tissues (blood and heart) - remain poorly understood. A deeper understanding of the tissue-specific mutational outcomes of anthracyclines could yield promising biomarkers to improve survivorship care for survivors of cancer.
Methods : We assembled a cohort of untreated or anthracycline-treated tumor, blood, and heart samples. Tumors and blood were leveraged from childhood cancer patients enrolled in the SickKids Cancer Sequencing Program. Heart samples were obtained from cancer survivors who received anthracyclines and later developed severe cardiotoxicity that required a heart transplant. We sequenced the DNA of each tissue type to identify anthracycline-induced somatic mutations.
Results: Our initial results revealed minimal genome-wide mutational differences between anthracycline-treated versus untreated samples across all tissue types. We hypothesized that anthracyclines may cause localized mutagenesis in unique genomic topographies. Indeed, we found that anthracycline-treated tissues had a strong enrichment of somatic mutations in open chromatin of their respective cell of origin but differed based on the mutation type. Anthracycline-treated tumors had an enrichment of single nucleotide variants in promoters and introns, but depletion of deletions in exonic regions. However, leveraging matched blood samples from these cancer patients demonstrated that anthracycline-treated blood samples had an enrichment for deletions in open chromatin of various blood cell types. Despite the heart's non-proliferative capacity, anthracycline-treated hearts had a significant enrichment of insertion-deletions in fetal cardiomyocyte open chromatin and non-B DNA regions. Lastly, comparative analysis of the somatic mutational profiles of anthracycline-exposed hearts, tumors, and blood samples, we uncovered previously underappreciated tissue-specific mutational signatures.
Significance: This study is the first to characterize the tissue-specific genomic consequences of anthracyclines on tumors, blood, and heart. The early identification of high-risk patients will transform survivorship care, ensuring children with cancer do not merely survive their diagnosis - they thrive beyond it.
利益披露 Disclosure
M. J. Mahendralingam, None..
T. Wen, None..
B. Otlu, None..
S. Mital, None..
F. Billia, None.