SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes

Eric Letouzé, Roberto Rosati, Heloisa Komechen, Mabrouka Doghman, Laetitia Marisa, Christa Flück, Ronald R. De Krijger, Max M. Van Noesel, Jean Christophe Mas, Mara A.D. Pianovski, Gerard P. Zambetti, Bonald C. Figueiredo, Enzo Lalli

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

44 Citaten (Scopus)


CONTEXT: Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization.

OBJECTIVE: We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients.

RESULTS: We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being -4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and -4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development.

CONCLUSIONS: Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.

Originele taal-2Engels
Pagina's (van-tot)E1284-E1293
TijdschriftJournal of Clinical Endocrinology and Metabolism
Nummer van het tijdschrift7
StatusGepubliceerd - jul. 2012
Extern gepubliceerdJa


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