Endocrine Abstracts

Background: Adrenocortical tumors consist of benign adenomas (ACA) and highly malignant carcinomas (ACC) with a still incompletely understood pathogenesis. Our aim was to test, whether there is evidence for an adenoma-carcinoma sequence.

Patients and methods: High-resolution single nucleotide polymorphism (SNP) microarrays (Affymetrix SNP 6.0) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH) in 46 adrenocortical tumors (24 ACA and 22 ACC) matched with normal samples.

Results: Genomic clustering showed good separation between ACA and ACC samples, with the best partition for chromosome (chr) 5, which was highly amplified in 17/22 ACC. Of note, the median number of CNA per tumor was not significantly different between ACA and ACA (43.5 vs 132; P=n.s.). However, recurrent CNAs (observed in >2 samples, frequency >15%), the median number of large CNAs (>100 Kb) or CN losses, and the percentage of samples affected by cnLOH were significantly higher in ACC (3993 vs 98 recurrent CNAs; 62.5 vs 7 large CNA; 72.5 vs 5.5 CN losses; 90.9 vs 29.1% cases with cnLOH, P<0.05 for each). Interestingly, more than 70% of alternations found in ACA were also present in ACC, most of them being observed in chr 5p15.33, 9q32–34, 16p13.3, and 19p13.3 and involving among others 11 growth factors, 41 transcription factors, 16 protein kinases, and 11 oncogenes. In addition, Notch signaling was the most frequently altered pathway in both tumor entities. Finally, a CN gain at chr 11p15.5 (‘IGF2 locus’) appears to be an early alteration in a multi-step tumor progression (present in 25% of ACA), followed by loss of one allele leading as a second hit to a cnLOH with consecutively increased expression of the imprinted IGF2 gene only in malignant adrenal tumors.

Conclusion: Our results on genetic alterations support the concept of an adenoma-carcinoma sequence in adrenocortical carcinoma.