Abstract
Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
Highlights
Adrenocortical tumors consist of highly prevalent adenomas (ACA) and rare carcinomas (ACC), which both can be either endocrinologically silent or hormonally active
We here provide for the first time a genome-wide highresolution overview of chromosomal changes in a large series of adrenocortical tumors, including adenomas and carcinomas
In a previous pilot study we already observed in a small group of benign cortisol-secreting tumors frequent CN gains in newly reported chromosomal regions (i.e. 8q24.3, 11p15.5, Xq28) and promising candidate genes or pathways potentially involved in early tumorigenesis [40]
Summary
Adrenocortical tumors consist of highly prevalent adenomas (ACA) and rare carcinomas (ACC), which both can be either endocrinologically silent or hormonally active. We reported novel genes (i.e. HRAS, EPHA7, and SGK1) and pathways (i.e. Notch signalling pathway) that could be involved in early tumorigenesis [40] Another recent study on childhood adrenocortical tumors using SNP array profiling identified some amplified oncogenes and deleted tumor suppressor genes and demonstrated different oncogenic routes [41]. We used high-resolution SNP microarrays to investigate a larger series of benign and malignant adrenocortical tumors with the major aim to identify new candidate genes that could be suggestive for an adenoma-carcinoma sequence (i.e. alterations common between ACA and ACC). We intended to recognize new potential markers of malignancy or prognostic factors for ACC
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