Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma.
Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). 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 in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%-53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Xiang
X
Chen
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Armita
A
Bahrami
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Alberto
A
Pappo
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
John
J
Easton
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
James
J
Dalton
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Erin
E
Hedlund
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
David
D
Ellison
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Sheila
S
Shurtleff
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Gang
G
Wu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lei
L
Wei
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Matthew
M
Parker
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Michael
M
Rusch
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Panduka
P
Nagahawatte
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jianrong
J
Wu
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Shenghua
S
Mao
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Kristy
K
Boggs
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Heather
H
Mulder
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Donald
D
Yergeau
The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA.
Charles
C
Lu
The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA.
Li
L
Ding
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Michael
M
Edmonson
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Chunxu
C
Qu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jianmin
J
Wang
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yongjin
Y
Li
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Fariba
F
Navid
University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Najat C
NC
Daw
The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA.
Elaine R
ER
Mardis
The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA.
Richard K
RK
Wilson
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
James R
JR
Downing
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: jinghui.zhang@stjude.org.
Jinghui
J
Zhang
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: michael.dyer@stjude.org.
Michael A
MA
Dyer
D000293:Adolescent; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
D004273:DNA, Neoplasm