Genomic landscape of paediatric adrenocortical tumours

Emilia M. Pinto; Xiang Chen; John Easton; David Finkelstein; Zhifa Liu; Stanley Pounds; Carlos Rodriguez-Galindo; Troy C. Lund; Elaine R. Mardis; Richard K. Wilson; Kristy Boggs; Donald Yergeau; Jinjun Cheng; Heather L. Mulder; Jayanthi Manne; Jesse Jenkins; Maria J. Mastellaro; Bonald C. Figueiredo; Michael A. Dyer; Alberto Pappo; Jinghui Zhang; James R. Downing; Raul C. Ribeiro; Gerard P. Zambetti

doi:10.1038/ncomms7302

Genomic landscape of paediatric adrenocortical tumours

Emilia M. Pinto, Xiang Chen, John Easton, David Finkelstein, Zhifa Liu, Stanley Pounds, Carlos Rodriguez-Galindo, Troy C. Lund, Elaine R. Mardis, Richard K. Wilson, Kristy Boggs, Donald Yergeau, Jinjun Cheng, Heather L. Mulder, Jayanthi Manne, Jesse Jenkins, Maria J. Mastellaro, Bonald C. Figueiredo, Michael A. Dyer, Alberto PappoJinghui Zhang, James R. Downing, Raul C. Ribeiro, Gerard P. Zambetti

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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.

Original language	English (US)
Article number	6302
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7302
State	Published - Mar 2015

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© 2015 Macmillan Publishers Limited.

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Pinto, E. M., Chen, X., Easton, J., Finkelstein, D., Liu, Z., Pounds, S., Rodriguez-Galindo, C., Lund, T. C., Mardis, E. R., Wilson, R. K., Boggs, K., Yergeau, D., Cheng, J., Mulder, H. L., Manne, J., Jenkins, J., Mastellaro, M. J., Figueiredo, B. C., Dyer, M. A., ... Zambetti, G. P. (2015). Genomic landscape of paediatric adrenocortical tumours. Nature communications, 6, Article 6302. https://doi.org/10.1038/ncomms7302

Pinto, EM, Chen, X, Easton, J, Finkelstein, D, Liu, Z, Pounds, S, Rodriguez-Galindo, C, Lund, TC, Mardis, ER, Wilson, RK, Boggs, K, Yergeau, D, Cheng, J, Mulder, HL, Manne, J, Jenkins, J, Mastellaro, MJ, Figueiredo, BC, Dyer, MA, Pappo, A, Zhang, J, Downing, JR, Ribeiro, RC & Zambetti, GP 2015, 'Genomic landscape of paediatric adrenocortical tumours', Nature communications, vol. 6, 6302. https://doi.org/10.1038/ncomms7302

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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.",

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AU - Pappo, Alberto

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AU - Downing, James R.

AU - Ribeiro, Raul C.

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N2 - 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.

AB - 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.

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Genomic landscape of paediatric adrenocortical tumours

Abstract

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