REARRANGEMENTS AT THE 11P15 LOCUS AND OVEREXPRESSION OF INSULIN-LIKE GROWTH FACTOR-II GENE IN SPORADIC ADRENOCORTICAL TUMORS

Little is known about the pathophysiology of sporadic adrenocortical t umors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly, in adrenocortical t umors, associated with the Beckwith-Wiedemann syndrome and because ins ulin-like growth factor-II (IGF-II) is a crucial regulator of fetal ad renal 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 benig n adenomas (13 with Cushing's syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 lo cus, and six (four carcinomas and two adenomas) of them (28.5%) exhibi ted 11p15 structural abnormalities in tumor DNA (five, an uniparental disomy and one, a mosaicism). In a single case that could be further s tudied, a paternal isodisomy was observed. Very high IGF-II mRNA conte nts were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with unipare ntal 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 w ere highly frequent in malignant tumors, but found only in rare adenom as. These results in combination with evidence for overexpression of I GF-II from the 11p15.5 locus suggest that abnormalities in structure a nd/or expression of the IGF-II gene play a role as a late event of a m ultistep process of tumorigenesis.