Genomic landscape of paediatric adrenocortical tumours.
Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Emilia M
000000015567000X
EM
Pinto
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Xiang
X
Chen
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
John
J
Easton
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
David
D
Finkelstein
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Zhifa
Z
Liu
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Stanley
0000000291672114
S
Pounds
Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02215, USA.
Carlos
C
Rodriguez-Galindo
University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Troy C
TC
Lund
1] The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA [3] Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Elaine R
ER
Mardis
1] The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA [3] Department of Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Richard K
RK
Wilson
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Kristy
K
Boggs
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Donald
D
Yergeau
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Jinjun
J
Cheng
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Heather L
HL
Mulder
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Jayanthi
J
Manne
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Jesse
J
Jenkins
Boldrini Children's Research Hospital, Campinas 13083-210, Brazil.
Maria J
MJ
Mastellaro
Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80-250-200, Brazil.
Bonald C
BC
Figueiredo
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Michael A
MA
Dyer
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Alberto
A
Pappo
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Jinghui
J
Zhang
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
James R
JR
Downing
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Raul C
RC
Ribeiro
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Gerard P
GP
Zambetti
D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000075924:X-linked Nuclear Protein; D051176:beta Catenin / Q000235:genetics
C495270:CTNNB1 protein, human; C035170:IGF2 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein