Single nucleotide polymorphism array profiling as tool to discover new candidates in diagnosis and prognosis for adrenocortical tumors

Aims: Adrenocortical tumors consist of benign adenomas (ACA) and highly malignant carcinomas (ACC) with a still incompletely understood pathogenesis.

Aim: To discover new candidate genes involved in adrenocortical tumorigenesis and to identify new diagnostic markers.

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: A median of 43.5 CNAs per sample were identified in ACA and 132 in ACC (P = NS). CN losses and large CNAs (> 100 Kb) were more frequent in ACC (median per sample: 72.5 vs. 5.5 and 62.5 vs. 7, respectively). Recurrent CNA (frequency > 15%) were more abundant in ACC (n = 3993) than in ACA (n = 98 gains). Both LOH and cnLOH were more frequent in ACC (20/22 samples) than in ACA (7/24 samples) and correlated with tumor size (P < 0.01, r = 0.41). Genomic clustering showed good separation between ACA and ACC samples, with the best partition for chromosome 5, which was highly amplified in 19/22 ACC. A total of 112 frequent gains were common in ACA and ACC (mostly affected regions: 5p15.33, 9q32 – 34, 16p13.3, 16q24.3, 19p13.3 and Xq28) and involved among others 11 growth factors, 41 transcription factors, 16 protein kinases, and 11 oncogenes. Notch signaling was the most frequently altered pathway.

Conclusion: We identified new candidate genes and pathways, such as Notch signaling, common for both ACA and ACC suggesting a major role for this pathway in early tumorigenesis. Trisomy of chromosome 5, large CN losses and cnLOH events are specific for carcinomas and could serve as diagnostic markers for malignancy.