Genetic characterization of adrenocortical tumors
Author: Kjellman, Magnus
Date: 1999-01-29
Location: Kirurgiska klinikens föreläsningssal, huvudbyggnaden plan 4, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för kirurgisk vetenskap / Department of Surgical Science
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 suggests that proteolytic enzymes are
important for the malignant behaviour of ACT.
Issue date: 1999-01-08
Publication year: 1999
ISBN: 91-628-3358-8
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