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Nat Commun. 2015 Mar 6;6:6302. doi: 10.1038/ncomms7302.

Genomic landscape of paediatric adrenocortical tumours.

Author information

1
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
2
Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
3
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
4
Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02215, USA.
5
University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
6
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.
7
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.
8
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
9
Boldrini Children's Research Hospital, Campinas 13083-210, Brazil.
10
Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80-250-200, Brazil.
11
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
12
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Abstract

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.

PMID:
25743702
PMCID:
PMC4352712
DOI:
10.1038/ncomms7302
[Indexed for MEDLINE]
Free PMC Article

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