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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.


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Characterization and timing of chromosome 11 and 17 LOH in pediatric ACT. (a) Microsatellite analysis of chromosome 11p15 in the WES cohort. All cases with available parental DNA demonstrated selective loss of maternal chromosome 11p15 (n=8, purple). (b) Temporal order of chromosome 11p and 17p cn-LOH and accumulation of single nucleotide variations (SNVs) in SJACT002. Scatter plots show mutant allele fractions (MAFs) of somatic SNVs and their genomic positions (individual dots) combined with 2-D density plots of allelic imbalance (AI) values of germline heterozygous SNPs in cn-LOH regions of chromosomes 11p (left) and 17p (center). At right, AI values in cn-LOH regions of chromosomes 11p and 17p were compared with the MAF distribution of somatic SNVs in genome-wide cn-LOH regions. (c) A 3-D scatter plot summarizes the temporal order of cn-LOH of chromosomes 11p and 17p and somatic SNV accumulation in pediatric ACTs. Shown are median AI values for the chromosome 11p cn-LOH region, median AI values for the chromosome 17p cn-LOH region and median MAF of SNVs in genome-wide cn-LOH regions of 14 cases; SJACT002 and SJACT005 are labeled. See also Supplementary Fig. 7b.
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Figure 4: Characterization and timing of chromosome 11 and 17 LOH in pediatric ACT. (a) Microsatellite analysis of chromosome 11p15 in the WES cohort. All cases with available parental DNA demonstrated selective loss of maternal chromosome 11p15 (n=8, purple). (b) Temporal order of chromosome 11p and 17p cn-LOH and accumulation of single nucleotide variations (SNVs) in SJACT002. Scatter plots show mutant allele fractions (MAFs) of somatic SNVs and their genomic positions (individual dots) combined with 2-D density plots of allelic imbalance (AI) values of germline heterozygous SNPs in cn-LOH regions of chromosomes 11p (left) and 17p (center). At right, AI values in cn-LOH regions of chromosomes 11p and 17p were compared with the MAF distribution of somatic SNVs in genome-wide cn-LOH regions. (c) A 3-D scatter plot summarizes the temporal order of cn-LOH of chromosomes 11p and 17p and somatic SNV accumulation in pediatric ACTs. Shown are median AI values for the chromosome 11p cn-LOH region, median AI values for the chromosome 17p cn-LOH region and median MAF of SNVs in genome-wide cn-LOH regions of 14 cases; SJACT002 and SJACT005 are labeled. See also Supplementary Fig. 7b.

Mentions: Chromosome 11p LOH was also identified in 32 of the 35 ACTs (91%). Two BWS patients (SJACT009 and SJACT065) with germline 11p homozygosity, indicative of uniparental disomy (UPD), were excluded from the analysis as LOH could not be assessed (Supplementary Fig. 2 and Fig 4a). Furthermore, cn-LOH of chromosome 11p was demonstrated by WGS in 14 of the 18 informative ACTs (Supplementary Fig. 2). Microsatellite marker analysis of an additional 22 pediatric ACT cases from our independent comparison cohort revealed chromosome 11p LOH in 20 tumors (95%, as IPACTR004 was excluded due to UPD) (Supplementary Fig. 4c). Remarkably, 100% of the cases from the combined cohorts that underwent chromosome 11p15 LOH and had available parental DNA (n=23) selectively retained the paternal chromosome (P = 2.4 × 10−7, sign test) (Fig. 4a and Supplementary Fig. 4c).


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)

Characterization and timing of chromosome 11 and 17 LOH in pediatric ACT. (a) Microsatellite analysis of chromosome 11p15 in the WES cohort. All cases with available parental DNA demonstrated selective loss of maternal chromosome 11p15 (n=8, purple). (b) Temporal order of chromosome 11p and 17p cn-LOH and accumulation of single nucleotide variations (SNVs) in SJACT002. Scatter plots show mutant allele fractions (MAFs) of somatic SNVs and their genomic positions (individual dots) combined with 2-D density plots of allelic imbalance (AI) values of germline heterozygous SNPs in cn-LOH regions of chromosomes 11p (left) and 17p (center). At right, AI values in cn-LOH regions of chromosomes 11p and 17p were compared with the MAF distribution of somatic SNVs in genome-wide cn-LOH regions. (c) A 3-D scatter plot summarizes the temporal order of cn-LOH of chromosomes 11p and 17p and somatic SNV accumulation in pediatric ACTs. Shown are median AI values for the chromosome 11p cn-LOH region, median AI values for the chromosome 17p cn-LOH region and median MAF of SNVs in genome-wide cn-LOH regions of 14 cases; SJACT002 and SJACT005 are labeled. See also Supplementary Fig. 7b.
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Figure 4: Characterization and timing of chromosome 11 and 17 LOH in pediatric ACT. (a) Microsatellite analysis of chromosome 11p15 in the WES cohort. All cases with available parental DNA demonstrated selective loss of maternal chromosome 11p15 (n=8, purple). (b) Temporal order of chromosome 11p and 17p cn-LOH and accumulation of single nucleotide variations (SNVs) in SJACT002. Scatter plots show mutant allele fractions (MAFs) of somatic SNVs and their genomic positions (individual dots) combined with 2-D density plots of allelic imbalance (AI) values of germline heterozygous SNPs in cn-LOH regions of chromosomes 11p (left) and 17p (center). At right, AI values in cn-LOH regions of chromosomes 11p and 17p were compared with the MAF distribution of somatic SNVs in genome-wide cn-LOH regions. (c) A 3-D scatter plot summarizes the temporal order of cn-LOH of chromosomes 11p and 17p and somatic SNV accumulation in pediatric ACTs. Shown are median AI values for the chromosome 11p cn-LOH region, median AI values for the chromosome 17p cn-LOH region and median MAF of SNVs in genome-wide cn-LOH regions of 14 cases; SJACT002 and SJACT005 are labeled. See also Supplementary Fig. 7b.
Mentions: Chromosome 11p LOH was also identified in 32 of the 35 ACTs (91%). Two BWS patients (SJACT009 and SJACT065) with germline 11p homozygosity, indicative of uniparental disomy (UPD), were excluded from the analysis as LOH could not be assessed (Supplementary Fig. 2 and Fig 4a). Furthermore, cn-LOH of chromosome 11p was demonstrated by WGS in 14 of the 18 informative ACTs (Supplementary Fig. 2). Microsatellite marker analysis of an additional 22 pediatric ACT cases from our independent comparison cohort revealed chromosome 11p LOH in 20 tumors (95%, as IPACTR004 was excluded due to UPD) (Supplementary Fig. 4c). Remarkably, 100% of the cases from the combined cohorts that underwent chromosome 11p15 LOH and had available parental DNA (n=23) selectively retained the paternal chromosome (P = 2.4 × 10−7, sign test) (Fig. 4a and Supplementary Fig. 4c).

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