Endocrine Abstracts

Introduction: The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism (SNP) microarrays to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH) in cortisol-secreting adrenocortical adenomas (ACAs). We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion.

Methods: 15 cortisol-secreting ACAs with matched blood samples were investigated. The SNP arrays were performed by Affymetrix SNP 6.0 and paired data analysis by Partek Genomics Suite software. Gene ontology annotation, pathway, gene and protein network analyses were used to identify candidate genes.

Results: We detected 962 CNAs with a median of 18 CNAs per sample. Half of them involved non-coding chromosomal regions, 89% were <100 Kb and 28% were found in at least two samples. Most frequently gained segments were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≧20% of cases), most of them being identified in the same three ACAs. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent microalterations that each affected a single gene (31 gains and 15 losses), including some genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found.

Conclusion: Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting ACAs and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.