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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123 Scopus citations

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

Bibliographical note

Funding Information:
We thank the St Jude Children’s Research Hospital Hartwell Center, Tissue Resources Core Facility, Marc Valentine and the Cytogenetics Laboratory, and Pathology Department for expert assistance and Drs Charles Mullighan, Kathryn Roberts and Evan Parganas for assistance with figures. We thank Drs Gad B. Kletter, Andres Yunes and Ana Luisa Seidinger for clinical samples. We thank Sharon Naron for scientific edition. This work was supported by Cancer Center Support grant CA21765 and grants EY014867, EY018599 and CA168875 (M.A.D.) from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC). Whole-genome sequencing was supported as part of the St Jude Children’s Research Hospital– Washington University Pediatric Cancer Genome Project. M.A.D. is a Howard Hughes Medical Institute Investigator.

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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, [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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title = "Genomic landscape of paediatric adrenocortical tumours",

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.",

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

note = "Funding Information: We thank the St Jude Children{\textquoteright}s Research Hospital Hartwell Center, Tissue Resources Core Facility, Marc Valentine and the Cytogenetics Laboratory, and Pathology Department for expert assistance and Drs Charles Mullighan, Kathryn Roberts and Evan Parganas for assistance with figures. We thank Drs Gad B. Kletter, Andres Yunes and Ana Luisa Seidinger for clinical samples. We thank Sharon Naron for scientific edition. This work was supported by Cancer Center Support grant CA21765 and grants EY014867, EY018599 and CA168875 (M.A.D.) from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC). Whole-genome sequencing was supported as part of the St Jude Children{\textquoteright}s Research Hospital– Washington University Pediatric Cancer Genome Project. M.A.D. is a Howard Hughes Medical Institute Investigator. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = mar,

doi = "10.1038/ncomms7302",

language = "English (US)",

volume = "6",

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T1 - Genomic landscape of paediatric adrenocortical tumours

AU - Pinto, Emilia M.

AU - Chen, Xiang

AU - Easton, John

AU - Finkelstein, David

AU - Liu, Zhifa

AU - Pounds, Stanley

AU - Rodriguez-Galindo, Carlos

AU - Lund, Troy C.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Boggs, Kristy

AU - Yergeau, Donald

AU - Cheng, Jinjun

AU - Mulder, Heather L.

AU - Manne, Jayanthi

AU - Jenkins, Jesse

AU - Mastellaro, Maria J.

AU - Figueiredo, Bonald C.

AU - Dyer, Michael A.

AU - Pappo, Alberto

AU - Zhang, Jinghui

AU - Downing, James R.

AU - Ribeiro, Raul C.

AU - Zambetti, Gerard P.

N1 - Funding Information: We thank the St Jude Children’s Research Hospital Hartwell Center, Tissue Resources Core Facility, Marc Valentine and the Cytogenetics Laboratory, and Pathology Department for expert assistance and Drs Charles Mullighan, Kathryn Roberts and Evan Parganas for assistance with figures. We thank Drs Gad B. Kletter, Andres Yunes and Ana Luisa Seidinger for clinical samples. We thank Sharon Naron for scientific edition. This work was supported by Cancer Center Support grant CA21765 and grants EY014867, EY018599 and CA168875 (M.A.D.) from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC). Whole-genome sequencing was supported as part of the St Jude Children’s Research Hospital– Washington University Pediatric Cancer Genome Project. M.A.D. is a Howard Hughes Medical Institute Investigator. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/3

Y1 - 2015/3

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

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