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Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression
F Wilkin1, N Gagné, J Paquette
1Sainte-Justine Hospital Research Center, Department of Pediatrics, Université de Montréal, Québec, Canada.
Abstract:
It has been previously shown that adrenocortical tumors (ACT) in adults exhibit structural abnormalities in tumor DNA in approximately 30% of cases. These abnormalities involve chromosome 11p15 and include loss of heterozygosity, paternal isodisomy, and overexpression of the gene for insulin-like growth factor II (IGF2), correlating with DNA demethylation at this locus. It has been hypothesized that these events occur late in the tumorigenic process in adults and seem to correlate with a worse prognosis. We present 4 pediatric cases of ACT diagnosed at 2.5 yr, 10 months, 12 yr, and 2.2 yr. All 4 patients presented with virilization, and 1 patient also showed signs and symptoms of glucocorticoid excess. The youngest patient's maternal aunt had surgical excision of a more than 15-cm ACT 18 yr previously, but the aunt is doing well at age 23 yr. They all had surgical removal of their tumors. The 2.5-yr-old child also received chemotherapy and radiotherapy because of capsular rupture and, after 3 local recurrences, died 3.3 yr after initial presentation. We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis. All 4 tumors (100%) showed a combination of structural abnormalities at the 11p15 locus with mosaic loss of heterozygosity involving 11p. All tumors also had significantly increased IGF2 messenger ribonucleic acid levels relative to normal adrenal (up to 36-fold) and significant IGF2 demethylation (mean, 87%). H19 messenger ribonucleic acid levels were undetectable in 3 of 4 tumors, explained in part by mosaic loss of the actively expressed maternal allele for this imprinted gene. By immunohistochemistry we were able to confirm increased IGF-II peptide levels within the tumor tissue in 10 pediatric patients, including the 4 patients described above. Concomitantly, we also observed nuclear accumulation of p53, suggesting somatic mutations. For the 10-month-old patient, sequencing revealed a p53 germline mutation. We therefore conclude that in pediatric ACT, structural abnormalities of tumor DNA and IGF2 overexpression as well as p53 mutations are very common and are therefore less useful for prognosis than in adults. Our findings support the theory that pediatric ACT, whose IGF2 expression and steroidogenesis evoke the phenotype of the fetal adrenal cortex, may arise because of defective apoptosis.
Insights
Pediatric adrenocortical tumors (ACT) frequently show 11p abnormalities and IGF2 overexpression, unlike in adults. These common genetic changes in pediatric ACT may stem from defective apoptosis, suggesting a different developmental pathway.
Area of Science:
- Endocrinology
- Pediatric Oncology
- Cancer Genetics
Background:
- Adrenocortical tumors (ACT) in adults show DNA abnormalities in ~30% of cases, often involving chromosome 11p15, paternal isodisomy, and IGF2 overexpression.
- These adult ACT abnormalities are hypothesized to occur late in tumorigenesis and correlate with poorer prognosis.
Observation:
- This study investigated 4 pediatric ACT cases, all presenting with virilization, and one with glucocorticoid excess.
- All pediatric tumors (100%) exhibited 11p structural abnormalities, mosaic loss of heterozygosity, significantly increased IGF2 mRNA (up to 36-fold), and IGF2 demethylation.
- H19 mRNA was undetectable in 3/4 tumors, and p53 nuclear accumulation was observed in 10 pediatric patients, with one case showing a p53 germline mutation.
Findings:
- Pediatric ACT universally display structural DNA abnormalities at 11p15, increased IGF2 expression, and demethylation.
- p53 mutations are common in pediatric ACT, contrasting with their later occurrence and prognostic significance in adult ACT.
- The genetic profile of pediatric ACT, including IGF2 overexpression, mimics the fetal adrenal cortex, suggesting a developmental origin possibly linked to defective apoptosis.
Implications:
- The high frequency of 11p abnormalities, IGF2 overexpression, and p53 mutations in pediatric ACT suggests these are early events, unlike in adults.
- These findings indicate that these genetic alterations are less useful as prognostic markers in pediatric ACT compared to adult ACT.
- The study supports the hypothesis that pediatric ACT may arise from defective apoptosis, leading to IGF2 overexpression and a phenotype resembling the fetal adrenal cortex.