Human Molecular Genetics, Vol 7, 895-903, Copyright © 1998 by Oxford University Press
P Karnik, M Paris, BR Williams, G Casey, J Crowe and P Chen
Chromosome 11p15 has attracted considerable attention because of the
biological importance of this region to human disease. Apart from being an
important tumor suppressor locus showing loss of heterozygosity (LOH) in
several adult and childhood cancers, 11p15 has been shown by linkage
analysis to harbor the gene(s) for the Beckwith-Wiedemann syndrome.
Furthermore, the clustering of known imprinted genes in the 11p15.5 region
suggests that the target gene may also be imprinted. However, positional
cloning efforts to identify the target genes have been complicated by the
large size (approximately 10 Mb) and complexity of LOH at 11p15. Here, we
have analyzed 94 matched normal and breast tumor samples using 17
polymorphic markers that map to 11p15.5-15.4. We have defined precisely the
location of a breast tumor suppressor gene between the markers D11S1318 and
D11S4088 (approximately 500 kb) within 11p15.5. LOH at this region occurred
in approximately 35-45% of breast tumors analyzed. In addition, we have
fine-mapped a second, critical region of LOH, that spans the markers
D11S1338-D11S1323 (approximately 336 kb) at 11p15.5-p15.4, that is lost in
approximately 55-60% of breast tumors. There is a striking correlation
between the loss of the two 11p loci and the clinical and histopathological
features of breast tumors. LOH at region 1 correlated significantly (P =
0.016) with early events in malignancy and invasiveness. In contrast, the
loss of the more proximal region 2, is highly predictive (P = 0.012) of
aggressive metastatic disease. Thus, two distinct tumor suppressor loci on
chromosome 11p15 may contribute to tumor progression and metastasis in
breast cancer. The fine mapping of this intriguing chromosomal region
should facilitate the cloning of the target genes and provide critical
clues to understanding the mechanisms that contribute to the evolution of
adult and childhood cancers.
ARTICLES
Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. karnikp@cesmtp.ccf.org
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