Single nucleotide polymorphism array profiling of adrenocortical tumors: evidence for an adenoma carcinoma sequence?

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.

An Adrenocortical Carcinoma Evolving from A Small Adrenal Incidentaloma after Years of Latency

“…Bernard et al (13) reported a resected adrenal lesion consisting of an ACC embedded within an adenoma and demonstrated in the ACC component multiple genetic alterations, including loss of heterozygosity of the p53 tumor suppressor locus and uniparental disomy of the insulin-like growth factor 2 (IGF2) locus and overexpression of IGF2 (13). A microarray study of human adrenocortical tumors (14) showed that large copy number losses were more common in ACCs than adenomas, while copy number gains were seen in both ACCs and adenomas, and involved several pathways known to enhance tumorigenicity (e.g., Wnt signaling), suggesting some common tumorigenesis events (14). Presumably, acquired stochastic genetic events can radically alter behaviors of previously 'benign' AIs.…”

The Genetics of Adrenocortical Tumors

“…116 Chromosomal alterations in ACC have been well characterized by different approaches: by conventional CGH, 117-119 by CGH array, [120][121][122] and, recently, by SNP array. 78,123 Alterations in copy numbers in ACCs are considerably higher in comparison with benign tumors. 120 If the alteration of certain loci is inconstant, copy number gains involving chromosomes 5, 7, 12, and 20 and losses in chromosome 22 were more often reported (see Fig.…”

“…Copy-neutral LOH detected by SNP array occurs in 30% to 90% of ACC. 78,123 SNP array allows the identification of gene amplification or deletion. In the European cohort of ACC, these alterations have been found in the locus of TERT, CD4, CDKN2A, RB1, and ZNFR3 (see earlier discussion) and in the locus 3q13.1 and 4q34.3 where the long noncoding RNA LOC285194 and LINC00290 are respectively located.…”

Adrenocortical Growth and Cancer

“…Ronchi et al investigated 24 ACA and 22 ACC by single nucleotide polymorphism (SNP) arrays (279). SNP profiling, including the most altered chomosomes (1, 5, 7, and 12), may differentiate malignant from benign ACTs.…”