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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

Somatic ATRX mutations and telomere analysis of pediatric adrenocortical tumors. (a) Distribution of non-silent single nucleotide variations in ATRX (blue dots: nonsense mutations; red dot: missense mutation). (b) Wiggle plots showing internal deletion of multiple exons in ATRX gene in SJACT005, SJACT062, and SJACT069 (diagnostic tumor [D] and germline [G] samples). (c) Relative telomere length determined by WGS in pediatric ACTs vs. matched germline samples. (d) Images of tumor samples hybridized with the telomeric FISH (red) and chromosome 4p (green) probes and stained with DAPI to visualize the nucleus (blue). High magnification views show the large, ultrabright signal in ATRX-mutant adrenocortical tumor cells (SJACT007). Scale bars, 1 μm.
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Figure 2: Somatic ATRX mutations and telomere analysis of pediatric adrenocortical tumors. (a) Distribution of non-silent single nucleotide variations in ATRX (blue dots: nonsense mutations; red dot: missense mutation). (b) Wiggle plots showing internal deletion of multiple exons in ATRX gene in SJACT005, SJACT062, and SJACT069 (diagnostic tumor [D] and germline [G] samples). (c) Relative telomere length determined by WGS in pediatric ACTs vs. matched germline samples. (d) Images of tumor samples hybridized with the telomeric FISH (red) and chromosome 4p (green) probes and stained with DAPI to visualize the nucleus (blue). High magnification views show the large, ultrabright signal in ATRX-mutant adrenocortical tumor cells (SJACT007). Scale bars, 1 μm.

Mentions: ATRX encodes a helicase that functions in chromatin remodeling and telomere structural maintenance, and it cooperates with DAXX to incorporate the histone variant H3.3 into chromatin13. ATRX somatic nonsense mutations and SVs deleting multiple exons were identified by WGS in 6 of 19 ACTs (32%), all of which were associated with germline TP53 mutations (Figs. 1a and 2a,b). An ATRX somatic missense mutation (R2164S) was also identified by WES in the case with somatic homozygous deletion of TP53 (Fig. 2a and Supplementary Fig. 3b). No mutations were detected in the coding region of DAXX or TERT by WGS or WES. Furthermore, no mutations were identified in the TERT core promoter by targeted Sanger sequencing. Although broad regional amplification encompassing the TERT locus was observed in 13 of the 19 WGS cases (68%), no TERT expression was detected by RNA-seq.


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)

Somatic ATRX mutations and telomere analysis of pediatric adrenocortical tumors. (a) Distribution of non-silent single nucleotide variations in ATRX (blue dots: nonsense mutations; red dot: missense mutation). (b) Wiggle plots showing internal deletion of multiple exons in ATRX gene in SJACT005, SJACT062, and SJACT069 (diagnostic tumor [D] and germline [G] samples). (c) Relative telomere length determined by WGS in pediatric ACTs vs. matched germline samples. (d) Images of tumor samples hybridized with the telomeric FISH (red) and chromosome 4p (green) probes and stained with DAPI to visualize the nucleus (blue). High magnification views show the large, ultrabright signal in ATRX-mutant adrenocortical tumor cells (SJACT007). Scale bars, 1 μm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4352712&req=5

Figure 2: Somatic ATRX mutations and telomere analysis of pediatric adrenocortical tumors. (a) Distribution of non-silent single nucleotide variations in ATRX (blue dots: nonsense mutations; red dot: missense mutation). (b) Wiggle plots showing internal deletion of multiple exons in ATRX gene in SJACT005, SJACT062, and SJACT069 (diagnostic tumor [D] and germline [G] samples). (c) Relative telomere length determined by WGS in pediatric ACTs vs. matched germline samples. (d) Images of tumor samples hybridized with the telomeric FISH (red) and chromosome 4p (green) probes and stained with DAPI to visualize the nucleus (blue). High magnification views show the large, ultrabright signal in ATRX-mutant adrenocortical tumor cells (SJACT007). Scale bars, 1 μm.
Mentions: ATRX encodes a helicase that functions in chromatin remodeling and telomere structural maintenance, and it cooperates with DAXX to incorporate the histone variant H3.3 into chromatin13. ATRX somatic nonsense mutations and SVs deleting multiple exons were identified by WGS in 6 of 19 ACTs (32%), all of which were associated with germline TP53 mutations (Figs. 1a and 2a,b). An ATRX somatic missense mutation (R2164S) was also identified by WES in the case with somatic homozygous deletion of TP53 (Fig. 2a and Supplementary Fig. 3b). No mutations were detected in the coding region of DAXX or TERT by WGS or WES. Furthermore, no mutations were identified in the TERT core promoter by targeted Sanger sequencing. Although broad regional amplification encompassing the TERT locus was observed in 13 of the 19 WGS cases (68%), no TERT expression was detected by RNA-seq.

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