Genomic landscape of pediatric adrenocortical tumors

Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyze 37 adrenocortical tumors (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 tumors. 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 tumor-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 pediatric ACT and outline a hypothetical model of pediatric adrenocortical tumorigenesis. Adrenocortical tumors (ACTs) are rare1. A good outcome, as with most pediatric embryonal tumors, requires early diagnosis and complete surgical resection. Children with locally advanced or metastatic disease have a very poor prognosis, even with surgery and intensive chemotherapy2. Childhood ACT is often associated with germline TP53 mutations (Li-Fraumeni syndrome, LFS)3 or constitutional genetic and/or epigenetic alterations affecting chromosome 11p15 (Beckwith-Wiedemann syndrome, BWS)4. Both LFS and BWS have highly variable phenotypes, which include susceptibility to ACT and other embryonal malignancies5. The factors contributing to sporadic pediatric ACTs are unknown, although the similarity of these cases to those with a constitutional predisposition suggests a common mechanism of tumorigenesis1. ACT is uniquely amenable to molecular studies relevant to pediatric embryonal neoplasms in general. First, the marked clinical endocrine manifestations of ACT (e.g., virilization and Cushing syndrome) allow access to tumor tissue at an early disease stage. Second, ACT shares the epidemiological and molecular features of embryonal tumors5. Finally, a cluster of ACTs arising from a founder TP53 mutation (R337H) in southern Brazil allows biologic, prognostic and therapeutic studies in a relatively large group of cases with a common predisposing factor6–9. Staging of pediatric ACT is based on tumor size and evidence of residual tumor after surgery1. Histopathologic classification criteria, which have been invaluable in distinguishing adenoma (benign) from carcinoma (malignant) in adult ACTs10, have a limited role in guiding therapeutic decisions in pediatric ACTs, the great majority of which are classified as carcinomas or histology of undetermined malignant potential11–12. To Pinto et al. Page 2 Nat Commun. Author manuscript; available in PMC 2015 September 06. A uhor M anscript