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Medizin - Open Access LMU - Teil 11/22 Podcast
Clonal Composition of Human Adrenocortical Neoplasms

Clonal Composition of Human Adrenocortical Neoplasms

Medizin - Open Access LMU - Teil 11/22 vor 32 Jahren

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The mechanisms of tumorigenesis of adrenocortical neoplasms are
still not understood. Tumor formation may be the result of
spontaneous transformation of adrenocortical cells by somatic
mutations. Another factor stimulating adrenocortical cell growth
and potentially associated with formation of adrenal adenomas and,
less frequently, carcinomas is the chronic elevation of
proopiomelanocortin-derived peptides in diseases like
ACTH-dependent Cushing's syndrome and congenital adrenal
hyperplasia. To further investigate the pathogenesis of
adrenocortical neoplasms, we studied the clonal composition of such
tumors using X-chromosome inactivation analysis of the highly
polymorphic region Xcen-Xp11.4 with the hybridization probe M27ß,
which maps to a variable number of tandem repeats on the
X-chromsome. In addition, polymerase chain reaction amplification
of a phosphoglycerokinase gene polymorphism was performed. After
DNA extraction from tumorous adrenal tissue and normal leukocytes
in parallel, the active X-chromosome of each sample was digested
with the methylation-sensitive restriction enzyme HpaII. A second
digestion with an appropriate restriction enzyme revealed the
polymorphism of the region Xcen-Xp11.4 and the phosphoglycerokinase
locus. Whereas in normal polyclonal tissue both the paternal and
maternal alleles are detected, a monoclonal tumor shows only one of
the parental alleles. A total of 21 female patients with adrenal
lesions were analyzed; 17 turned out to be heterozygous for at
least one of the loci. Our results were as follows: diffuse (n = 4)
and nodular (n = 1) adrenal hyperplasia in patients with
ACTH-dependent Cushing's syndrome, polyclonal pattern;
adrenocortical adenomas (n = 8), monoclonal (n = 7), as well as
polyclonal (n = 1); adrenal carcinomas (n = 3), monoclonal pattern.
One metastasis of an adrenocortical carcinoma showed a pattern most
likely due to tumor-associated loss of methylation. In the special
case of a patient with bilateral ACTH-independent macronodular
hyperplasia, diffuse hyperplastic areas and a small nodule showed a
polyclonal pattern, whereas a large nodule was monoclonal. We
conclude that most adrenal adenomas and carcinomas are monoclonal,
whereas diffuse and nodular adrenal hyperplasias are polyclonal.
The clonal composition of ACTH-independent massive macronodular
hyperplasia seems to be heterogeneous, consisting of polyclonal and
monoclonal areas.