Genetic characterization of adrenocortical tumors

Abstract

Adrenocortical cancer is a rare tumor form. However, adrenal tumors are today often found incidentally when using imaging techniques on the upper abdomen and should then be investigated. With the advance in molecular understanding of cancer new approaches to manage the disease may become available. We screened malignant and benign adrenocortical tumors (ACT) for gross genetic alterations using comparative genomic hybridization and microsatellite markers with the aim to find chromosomal regions that may harbour oncogenes, tumor suppressor genes, or mutator genes. Chromosomes 4 and 5 were found to possibly harbour oncogenes whereas chromosomes 2, 11, 17 and 18 may harbour tumor suppressor genes of importance for the development and progression of ACT. Furthermore, the study indicates that fundamental genetic changes take place in ACT larger than 4 cm.

Because the tumor syndromes, Carney complex (CC) and Multiple endocrine neoplasia type I (MEN 1), are located on chromosome 2p16 and 11q13, respectively, these regions were further investigated. A one centi Morgan region, located distal to the CC locus, was defined by deletion mapping and may harbour TSGs of importance for the malignant transition of ACT. Furthermore, the 11q13 locus was frequently deleted in malignant ACT but no mutations were found in the MEN1 gene. It will be appropriate to investigate the transcriptional regulating region of the gene as well as epigenetic changes, such as the imprinting status. However, another gene(s) with TSG function may show to cause the frequent percentage of deletions at this locus.

Another candidate gene, the IGF2 gene (11pl5) has been suggested to contribute to neoplastic cell proliferation and increase of its transcripts has been found in ACT. Studies of the IGF2 gene showed two novel splicing events which was also found in a Hep 3B cell line. The function of these splicing events is unknown.

The suspected high prevalence of undiagnosed mild congenital adrenal hyperplasia (CAH), together with the high frequency of sporadic ACT in the population, has led to the speculation that mild undiagnosed CAH, or the heterozygous carrier state, is a predisposing factor for the development and/or progression of this tumor form. To investigate if mild CAH may be overrepresented in patients with apparently sporadic ACT we screened for constitutional mutations in the CYP21 gene. As no mutations were found we conclude that patients with ACT do not need to be screened for CAH.

Gelatinase A is a metalloproteinase important in the process of tumor invasion and metastasis. Analyzes of mRNA expression of gelatinase A and its activator MT1-MMP showed increased levels in malignant as compared with benign ACT. These findings suggest that proteolytic enzymes are important for the malignant behaviour of ACT.