Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma.
Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma.
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DOI：
10.1016/j.celrep.2014.03.003
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发表时间：
2014-04-10
期刊：
影响因子：
8.8
通讯作者：
St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
中科院分区：
文献类型：
--
作者：
Chen X;Bahrami A;Pappo A;Easton J;Dalton J;Hedlund E;Ellison D;Shurtleff S;Wu G;Wei L;Parker M;Rusch M;Nagahawatte P;Wu J;Mao S;Boggs K;Mulder H;Yergeau D;Lu C;Ding L;Edmonson M;Qu C;Wang J;Li Y;Navid F;Daw NC;Mardis ER;Wilson RK;Downing JR;Zhang J;Dyer MA;St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
骨肉瘤是一种间质来源的肿瘤，具有成骨分化的特征。复发或转移性疾病患者的预后非常差。为了确定儿童骨肉瘤的体细胞突变情况，我们对发现队列中的20个骨肉瘤肿瘤样本和匹配的正常组织（从19名患者中获得）以及验证队列中的13名患者的14个样本进行了全基因组DNA测序。我们的研究结果表明，儿童骨肉瘤的特点是多体细胞染色体病变，包括结构变异（SV）和拷贝数改变（CNA）。此外，单核苷酸变异（SNV）在50%的肿瘤中表现出称为“kataegis”的局部超突变模式。尽管骨肉瘤基因组中存在这些kataegis区域，但我们检测到相对较少的复发性SNV，只有当包括SV时，我们才确定骨肉瘤中突变的主要途径。我们在发现队列中的所有19名患者的肿瘤中鉴定了p53通路病变，其中9例是TP 53基因第一内含子的易位，导致基因失活。这种p53基因失活的机制在儿科癌症中的骨肉瘤中是独特的。在另外一组32例患者中，在其中29例肿瘤中发现TP 53基因改变。在TP 53之外，RB 1、ATRX和DLG 2基因在29-53%的肿瘤中显示出复发性体细胞改变（SNV和/或SV）。这些数据突出了全基因组测序在识别癌症基因组中可能使用其他方法遗漏的复发性体细胞改变方面的能力。
Osteosarcoma is a neoplasm of mesenchymal origin with features of osteogenic differentiation. Patients with recurrent or metastatic disease have a very poor prognosis. To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue (obtained from 19 patients) in the discovery cohort as well as 14 samples from 13 patients in the validation cohort. Our results demonstrate that pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). Moreover, single nucleotide variations (SNVs) exhibit a pattern of localized hypermutation called “kataegis” in 50% of the tumors. Despite these regions of kataegis across the osteosarcoma genomes, we detected relatively few recurrent SNVs, and only when SVs were included did we identify the major pathways that are mutated in osteosarcoma. We identified p53 pathway lesions in all 19 patient’s tumors in the discovery cohort, 9 of which were translocations in the first intron of the TP53 gene, leading to gene inactivation. This mechanism of p53 gene inactivation is unique to osteosarcoma among pediatric cancers. In an additional cohort of 32 patients, TP53 gene alterations were identified in 29 of those tumors. Beyond TP53, the RB1, ATRX and DLG2 genes showed recurrent somatic alterations (SNVs and/or SVs) in 29–53% of the tumors. These data highlight the power of whole-genome sequencing in identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.
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