Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.

Abstract

Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly, in adrenocortical tumors, associated with the Beckwith-Wiedemann syndrome and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, we looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing's syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing's syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, an uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis.

Distinct Transcriptional Profiles of Adrenocortical Tumors Uncovered by DNA Microarray Analysis

“…Select RNA and protein-based studies were performed to validate the array data; moreover, comparison of the array data to the published literature provides an additional and vital level of validation. For example, ample evidence exists that increased expression of IGF2 occurs in ACC 23 and this was robustly confirmed by this study. Furthermore, TOP2A has been reported to be up-regulated in ACC and used as a diagnostic marker 10,14 and was independently identified as one of the significantly up-regulated genes in this cohort of ACCs.…”

“…18 -20 The insulin-like growth factor II gene (IGF2) is involved in the pathogenesis of both familial ACCs, as is the case in Beckwith-Wiedemann syndrome, 21 as well as in sporadic ACCs. 22,23 Dysregulation or rearrangement at 11p15.5 results in significant up-regulation of IGF2 in ACC, resulting in an autocrine stimulatory loop. 24 Gene expression profiling provides the opportunity to assess the expression of thousands of genes simultaneously in a cohort of related tumors.…”

An Investigation of the Ligand Binding Properties and Negative Cooperativity of Soluble Insulin-like Growth Factor Receptors

“…Also, the IGF-1R is essential for transformation to a malignant phenotype (4). Interestingly, there is increasing evidence to support a role for IGF-II in a variety of cancers, where elevated IGF-II levels are associated with increased cancer risk (5)(6)(7)(8), reviewed in Ref. 3.…”

Assessment of p57^KIP2 Gene Mutation in Beckwith-Wiedemann Syndrome

“…Allelic loss of the 11p15 region in the leucocyte DNA of the patients was excluded by Southern blot analysis using 11p15 polymorphisms as previously described [18]. Fifteen samples from patients were analysed simultaneously with parental leucocyte DNA.…”