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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

Histopathological and genomic features of TP53-R337H associated ACTs. All tumors had a high mitotic rate (>5 per 50 high-power fields, H&E, 400X). Histology showed a vague nested and trabecular pattern with occasional unpatterned cellular sheets of variable size. Three cases (SJACT063, SJACT062 and SJACT069) had a high nuclear grade and marked cellular pleomorphism. SJACT070 showed occasional enlarged hyperchromatic nuclei with one or more prominent nucleoli. Necrotic cells and atypical mitotic figures (arrow) are identified in SJACT63 and SJACT69. Accumulation of genomic alterations illustrated by the Circos plots (bottom panels) paralleled an increase in tumor weight and correlated with a more aggressive tumor phenotype (Group 1 vs Group 2). Note: labels for gene disrupting SVs (SJACT063 and SJACT062) and non-coding mutations (SJACT069) were removed from the Circos plots.
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Figure 3: Histopathological and genomic features of TP53-R337H associated ACTs. All tumors had a high mitotic rate (>5 per 50 high-power fields, H&E, 400X). Histology showed a vague nested and trabecular pattern with occasional unpatterned cellular sheets of variable size. Three cases (SJACT063, SJACT062 and SJACT069) had a high nuclear grade and marked cellular pleomorphism. SJACT070 showed occasional enlarged hyperchromatic nuclei with one or more prominent nucleoli. Necrotic cells and atypical mitotic figures (arrow) are identified in SJACT63 and SJACT69. Accumulation of genomic alterations illustrated by the Circos plots (bottom panels) paralleled an increase in tumor weight and correlated with a more aggressive tumor phenotype (Group 1 vs Group 2). Note: labels for gene disrupting SVs (SJACT063 and SJACT062) and non-coding mutations (SJACT069) were removed from the Circos plots.

Mentions: WGS did not reveal any specific genetic alterations that distinguished ACTs harboring the founder TP53-R337H from tumors with other TP53 mutations. However, R337H tumors that had acquired an ATRX mutation (cases SJACT062 and SJACT069) clustered in Group 1 and exhibited an aggressive phenotype (Figs. 1 and 3). The remaining 8 R337H cases showed variable molecular profiles and disease stage (Fig. 1 and Supplementary Fig. 2). Figure 3 illustrates the relationship among histopathological features, tumor weight, stage and complexity of genomic abnormalities for four cases with the same predisposing TP53-R337H germline mutation.


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)

Histopathological and genomic features of TP53-R337H associated ACTs. All tumors had a high mitotic rate (>5 per 50 high-power fields, H&E, 400X). Histology showed a vague nested and trabecular pattern with occasional unpatterned cellular sheets of variable size. Three cases (SJACT063, SJACT062 and SJACT069) had a high nuclear grade and marked cellular pleomorphism. SJACT070 showed occasional enlarged hyperchromatic nuclei with one or more prominent nucleoli. Necrotic cells and atypical mitotic figures (arrow) are identified in SJACT63 and SJACT69. Accumulation of genomic alterations illustrated by the Circos plots (bottom panels) paralleled an increase in tumor weight and correlated with a more aggressive tumor phenotype (Group 1 vs Group 2). Note: labels for gene disrupting SVs (SJACT063 and SJACT062) and non-coding mutations (SJACT069) were removed from the Circos plots.
© Copyright Policy
Related In: Results  -  Collection

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Figure 3: Histopathological and genomic features of TP53-R337H associated ACTs. All tumors had a high mitotic rate (>5 per 50 high-power fields, H&E, 400X). Histology showed a vague nested and trabecular pattern with occasional unpatterned cellular sheets of variable size. Three cases (SJACT063, SJACT062 and SJACT069) had a high nuclear grade and marked cellular pleomorphism. SJACT070 showed occasional enlarged hyperchromatic nuclei with one or more prominent nucleoli. Necrotic cells and atypical mitotic figures (arrow) are identified in SJACT63 and SJACT69. Accumulation of genomic alterations illustrated by the Circos plots (bottom panels) paralleled an increase in tumor weight and correlated with a more aggressive tumor phenotype (Group 1 vs Group 2). Note: labels for gene disrupting SVs (SJACT063 and SJACT062) and non-coding mutations (SJACT069) were removed from the Circos plots.
Mentions: WGS did not reveal any specific genetic alterations that distinguished ACTs harboring the founder TP53-R337H from tumors with other TP53 mutations. However, R337H tumors that had acquired an ATRX mutation (cases SJACT062 and SJACT069) clustered in Group 1 and exhibited an aggressive phenotype (Figs. 1 and 3). The remaining 8 R337H cases showed variable molecular profiles and disease stage (Fig. 1 and Supplementary Fig. 2). Figure 3 illustrates the relationship among histopathological features, tumor weight, stage and complexity of genomic abnormalities for four cases with the same predisposing TP53-R337H germline mutation.

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