2 DISTINCT TUMOR-SUPPRESSOR LOCI WITHIN CHROMOSOME 11P15 IMPLICATED IN BREAST-CANCER PROGRESSION AND METASTASIS

Chromosome 11p15 has attracted considerable attention because of the b iological importance of this region to human disease. Apart from being an important tumor suppressor locus showing loss of heterozygosity (L OH) in several adult and childhood cancers, 11p15 has been shown by li nkage analysis to harbor the gene(s) for the Beckwith-Wiedemann syndro me. 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 com plicated by the large size (similar to 10 Mb) and complexity of LOH at 11p15. Here, we have analyzed 94 matched normal and breast tumor samp les using 17 polymorphic markers that map to 11p15.5-15.4. We have def ined precisely the location of a breast tumor suppressor gene between the markers D11S1318 and D11S4088 (similar to 500 kb) within 11p15.5. LOH at this region occurred in similar to 35-45% of breast tumors anal yzed. In addition, we have fine-mapped a second, critical region of LO H, that spans the markers D11S133-D11S1323 (similar to 336 kb) at 11p1 5.5-p15.4, that is lost in similar to 55-60% of breast tumors. There i s a striking correlation between the loss of the two 11p loci and the clinical and histopathological features of breast tumors. LOH at regio n 1 correlated significantly (P = 0.016) with early events in malignan cy 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 cont ribute to tumor progression and metastasis in breast cancer. The fine mapping of this intriguing chromosomal region should facilitate the cl oning of the target genes and provide critical clues to understanding the mechanisms that contribute to the evolution of adult and childhood cancers.