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Genomic landscape of paediatric adrenocortical tumours.

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 - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, 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.

No MeSH data available.


Related in: MedlinePlus

Association between molecular and clinicopathological features of pediatric adrenocortical tumors. (a) Upper panel: clinicopathological features of 19 patients in the WGS cohort. Center panel: genetic alterations, including mutational status of TP53 (R337H identified by asterisk), ATRX and CTNNB1; telomere length; number of structural variations (SVs); background mutation rate (BMR); chromothripsis and kataegis. Und: undetermined malignancy. Lower panel: RNA expression of selected genes involved in chromosomal segregation and cell cycle control. Three distinct tumor groups (labeled below) emerged from this analysis. Control: normal adrenocortical tissue. (b) Kaplan-Meier probability of event-free survival (exact log-rank test) of pediatric ACT patients in group 1 vs. others.
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Figure 1: Association between molecular and clinicopathological features of pediatric adrenocortical tumors. (a) Upper panel: clinicopathological features of 19 patients in the WGS cohort. Center panel: genetic alterations, including mutational status of TP53 (R337H identified by asterisk), ATRX and CTNNB1; telomere length; number of structural variations (SVs); background mutation rate (BMR); chromothripsis and kataegis. Und: undetermined malignancy. Lower panel: RNA expression of selected genes involved in chromosomal segregation and cell cycle control. Three distinct tumor groups (labeled below) emerged from this analysis. Control: normal adrenocortical tissue. (b) Kaplan-Meier probability of event-free survival (exact log-rank test) of pediatric ACT patients in group 1 vs. others.

Mentions: Germline TP53 mutations were present in 25 of the 37 patients (68%) in the combined WGS and WES cohorts, 12 of which were the Brazilian founder R337H mutation (Fig. 1a and Supplementary Fig. 3a). Somatic mutations (R175H, R273C, and a homozygous deletion of ~200 Kb of chromosome 17 encompassing TP53) were also identified in 3 of the 12 ACTs associated with wild-type germline TP53 (Supplementary Figs. 3a,b).


Genomic landscape of paediatric adrenocortical tumours.

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 - Nat Commun (2015)

Association between molecular and clinicopathological features of pediatric adrenocortical tumors. (a) Upper panel: clinicopathological features of 19 patients in the WGS cohort. Center panel: genetic alterations, including mutational status of TP53 (R337H identified by asterisk), ATRX and CTNNB1; telomere length; number of structural variations (SVs); background mutation rate (BMR); chromothripsis and kataegis. Und: undetermined malignancy. Lower panel: RNA expression of selected genes involved in chromosomal segregation and cell cycle control. Three distinct tumor groups (labeled below) emerged from this analysis. Control: normal adrenocortical tissue. (b) Kaplan-Meier probability of event-free survival (exact log-rank test) of pediatric ACT patients in group 1 vs. others.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352712&req=5

Figure 1: Association between molecular and clinicopathological features of pediatric adrenocortical tumors. (a) Upper panel: clinicopathological features of 19 patients in the WGS cohort. Center panel: genetic alterations, including mutational status of TP53 (R337H identified by asterisk), ATRX and CTNNB1; telomere length; number of structural variations (SVs); background mutation rate (BMR); chromothripsis and kataegis. Und: undetermined malignancy. Lower panel: RNA expression of selected genes involved in chromosomal segregation and cell cycle control. Three distinct tumor groups (labeled below) emerged from this analysis. Control: normal adrenocortical tissue. (b) Kaplan-Meier probability of event-free survival (exact log-rank test) of pediatric ACT patients in group 1 vs. others.
Mentions: Germline TP53 mutations were present in 25 of the 37 patients (68%) in the combined WGS and WES cohorts, 12 of which were the Brazilian founder R337H mutation (Fig. 1a and Supplementary Fig. 3a). Somatic mutations (R175H, R273C, and a homozygous deletion of ~200 Kb of chromosome 17 encompassing TP53) were also identified in 3 of the 12 ACTs associated with wild-type germline TP53 (Supplementary Figs. 3a,b).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, 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.

No MeSH data available.


Related in: MedlinePlus