Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis

Abstract

Genetic changes underlying the tumorigenesis of sporadic adrenocortical tumors are poorly characterized. To search for characteristic genomic imbalances involved in adrenocortical tumors, we examined 41 adrenocortical lesions (12 carcinomas, 23 adenomas, and 6 hyperplasias) by comparative genomic hybridization. Our results show that genetic alterations are more frequent in malignant than in benign lesions and that they rarely occur in hyperplastic lesions. The most frequent DNA copy number changes in adrenocortical carcinomas included losses of 1p21-31, 2q, 3p, 3q, 6q, 9p, and 11q14-qter, as well as gains and amplifications of 5q12, 9q32-qter, 12q, and 20q. The genomic aberrations prevalently occurring in adrenocortical adenomas were gains of 17q, 17p, and 9q32-qter. Gains found in 2 of 6 adrenocortical hyperplastic lesions involved chromosome 17 or 17q only. These data indicate that oncogenes determining the early tumorigenesis of adrenocortical tumors may exist on chromosome 17 and that the number of genomic alterations is closely associated with tumor behavior in adrenocortical tumors.

Figure 1.

Correlation between the number of genomic alterations and tumor size as analyzed by regression (r² = 0.4, P = 0.0001).

Figure 2.

Summary of all DNA copy number alterations detected by CGH in 23 sporadic adrenocortical adenomas and 6 hyperplasias (A) and 12 carcinomas (B). The vertical green lines on the right side of the chromosome ideograms indicate gains, the red on the left losses of the corresponding chromosomal regions. The blue lines indicate gains detected in adrenocortical hyperplastic lesions. Amplifications are indicated as solid green bars. C: Representative examples of CGH digital images and profiles illustrating DNA copy number changes of chromosomes 1 (1p loss and 1q gain), 9 (loss of 9p21-pter and 9q gain), 5 and 12 (amplifications), and 17 (gain). Tumor DNA was labeled using green-dUTP and normal reference DNA with red-dUTP. The color ratio values 0.8, 1.2 and 1.5 were used as thresholds for chromosomal losses, gains and amplifications, respectively. D: Representative results of FISH analysis. I–IV: interphase touch preparation of sporadic adrenocortical tumors investigated using specific centromeric probes for chromosome 17 (red) and chromosome 1 (green). I, normal diploid; II, monosomy of both chromosomes 17 and 1 (tumor 32); III, trisomy of chromosome 17 (tumor 29); IV, tetrasomy of chromosome 17 and trisomy of chromosome 1 (tumor 8). V: MEN1 gene (green signal) located to 11q13 on metaphase chromosomes from normal human lymphocytes. Red signal, centromeric marker of chromosome 11. VI: allelic loss of one copy of the MEN1 gene (tumor 38; one green signal).