Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
Department of Pediatrics, School of Medicine, Technical University of Munich; 80804 Munich, Germany.
Int J Mol Sci. 2022 May 5;23(9):5174. doi: 10.3390/ijms23095174.
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While p.P298S/A did not disrupt the formation of the cohesin complex, it altered gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While p.P298S/A did not disrupt the formation of the cohesin complex, it altered gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
黏连蛋白基因的体细胞功能丧失突变常与多种癌症类型相关，而胚系中的黏连蛋白破坏会导致黏连蛋白病，如科恩利亚-德-兰格综合征（CdLS）。在这里，我们在 482 名儿科癌症患者的总数据集发现了三个患有淋巴母细胞白血病或淋巴瘤的儿童中，存在黏连蛋白基因第 298 位氨基酸位置（p.P298S/A）的反复杂合性胚系突变。虽然 p.P298S/A 没有破坏黏合复合物的形成，但它改变了基因表达，DNA 损伤反应，并且原代患者成纤维细胞在照射和丝裂霉素 C 处理后显示出 G2/M 期阻滞增加。随后对健康人类骨髓的单细胞 RNA 测序分析证实，在造血过程中，不同的黏连蛋白基因模式上调，突出了增殖 B 和 T 细胞内表达的重要性。因此，我们的临床和功能数据表明，胚系变异可能导致儿童淋巴母细胞白血病或淋巴瘤，而不表现出 CdLS 表型。
