Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma
By Xiang Chen, A. Bahrami, A. Pappo, J. Easton, J. Dalton, Erin K. Hedlund, D. Ellison, S. Shurtleff, Gang Wu, Lei Wei and 21 more. Cell Reports, 2014
690 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Hematology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/b9ced0eaaa64c122eb5523887f88c032ebf57d78
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Citations in the corpus
- Current and future therapeutic approaches for osteosarcoma (2018, neutral): “genome through sequencing and microarray platforms [87,89].”
- Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. (2015, methodology): “When sequencing analyses are performed on osteosarcomas, regions of hypermutation called kataegis are frequently present.(40) Although alterations in p53 and Rb result in genetic instability, it is not clear if all of the complexity is driven by these alterations.”
- Translational biology of osteosarcoma (2014, background): “Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose.”