Magrath Justin W, Flinchum Dane A, Hartono Alifiani B, Goldberg Ilon N, Espinosa-Cotton Madelyn, Moroz Krzysztof, Cheung Nai-Kong V, Lee Sean B
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sarcoma. 2023 Jul 6;2023:6686702. doi: 10.1155/2023/6686702. eCollection 2023.
Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1-3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the downregulated gene set, suggesting the fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors.
促纤维组织增生性小圆细胞肿瘤（DSRCT）是一种由融合致癌基因引起的罕见儿科癌症。尽管对化疗有初始反应，但DSRCT的复发率超过80%，导致患者预后不良，5年生存率仅为15%-25%。由于DSRCT罕见，样本稀缺是理解DSRCT生物学特性和开发有效疗法的一个障碍。利用一对新的原发性和复发性DSRCT，我们展示了首张DSRCT基因组断点图谱，并首次比较了原发性和复发性DSRCT之间的基因表达变化。我们的基因组断点图谱包括之前唯一发表的DSRCT基因组断点、来自我们新的原发性/复发性DSRCT对的断点，以及五个可用DSRCT细胞系和另外五个DSRCT的断点。所有映射的断点都是独特的，大多数断点包含1-3个碱基对的微同源性，表明微同源性介导的末端连接是易位融合的机制，并为DSRCT的病因提供了新见解。通过RNA测序分析，我们确定了原发性和复发性DSRCT之间的基因和通路变化。复发性肿瘤中上调的通路包括几个DNA修复和mRNA剪接相关通路，而下调的通路包括免疫系统功能和粘着斑。我们进一步发现，与原发性肿瘤相比，复发性肿瘤中上调基因集的表达更高，下调基因集的表达更低，这表明融合在复发性肿瘤中继续发挥重要作用。所确定的通路，包括DNA修复上调和免疫系统功能下调，可能有助于解释DSRCT的高复发率，并可用于增进对DSRCT生物学特性的理解，以及确定有助于预防复发和治疗复发性肿瘤的新疗法。
