Bradley J. Quade,
M.D., Ph.D., Center Clinical Director of Pathology
Uterine smooth muscle
tumors include common leiomyomas, infrequent leiomyosarcomas, and
unusual "quasi-malignant" proliferations such as
disseminated peritoneal and intravenous leiomyomatosis. Distinction of
uterine leiomyosarcoma from benign smooth muscle tumors is not always
possible on morphological grounds. Some clinically benign smooth
muscle tumors paradoxically have "malignant" features (e.g.,
extreme atypia or dissemination within the peritoneum or vascular
system), while many clinically malignant tumors may have strikingly
subtle features. This difficulty in predicting clinical behavior
solely based on morphological phenotype is reflected in diagnostic
terms such as "smooth muscle tumor of uncertain malignant
potential" and "atypical leiomyoma with recurring
potential". The major goal of our research is to define the
genetic factors that determine the clinical and morphological
phenotypes of uterine smooth muscle tumors.
Uterine leiomyosarcomas
can be distinguished from benign leiomyomas by cytogenetic analysis.
Leiomyosarcomas typically have complex cytogenetic abnormalities.
Karyotypes show both numerical and structural aberrations. These
aberrations are often unstable, resulting in significant variation
from metaphase to metaphase. In contrast to leiomyosarcomas, benign
leiomyomas have simple cytogenetic abnormalities in approximately 40%
of tumors. The most common aberrations in leiomyomas include a
translocation between chromosome 12 and 14 and deletions of the long
arm of chromosome 7. The gene on chromosome 12 has been identified as
the DNA architectural factor HMGIC.
To understand better the
molecular pathogenetic distinction(s) between these tumors, we are
analyzing expression of HMGIC in leiomyomas, leiomyosarcomas
and their variants. We are also cloning HMGIC's translocation
partner on chromosome. When our positional cloning of the
translocation partner on chromosome 14 has been completed, we will
also analyze its expression in benign and malignant smooth muscle
tumors.
Cytogenetic complexity
precludes a positional cloning approach for identifying genes
important in leiomyosarcoma. We proposed that genomic instability
apart from chromosomal aberrations might be manifested preferentially
in leiomyosarcoma. Our preliminary results demonstrate frequent and
selective loss of heterozygosity (LOH) for markers on chromosome 10 in
leiomyosarcoma compared to other chromosomes. In contrast to
leiomyosarcoma, LOH (at any locus) is not a feature of leiomyomas.
Frequent LOH on chromosome 10 in leiomyosarcomas may point to a tumor
suppressor gene.
