Detailed deletion mapping with a refined physical map of 7q31 localizes a putative tumor suppressor gene for breast cancer in the region of MET.

In breast cancer, loss of heterozygosity (LOH) has been described on the long arm of chromosome 7 at band q31, suggesting the presence of a tumor suppressor gene in this region. To define the deleted region, we analysed 73 cases of breast cancer and matched normal DNAs with 17 polymorphic markers. A minimal area of LOH was identified as the chromosomal interval flanked by markers D7S687 and metH, spanning a segment of 2 Mb on chromosome 7q31. Of the 73 breast cancer patients studied, all were informative for at least one marker in this region and nine patients showed LOH at one or more loci (12.3%). To define the physical size of the deletion and to ensure the correct interpretation of the LOH deletion studies, we redefined the physical map of markers within this region of 7q31. We present a new physical order for markers at 7q31. More significantly, we have mapped the minimum deletion of 7q31 in the breast cancers studied to date to a physical distance of 1000 kb, contained on a single YAC clone, which includes the MET receptor tyrosine kinase but no other known genes.

Human breast cancer: genetic alterations in the MET gene region.

OBJECTIVE: to test whether the MET gene at chromosome 7q31, which encodes a receptor protein (tyrosine kinase) related to normal histological differentiation, undergoes structural changes in breast cancer. A previous study reported somatic alterations detected as loss of heterozygosity (LOH) at this locus in breast cancer. DESIGN: Analysis of DNA from tumours and matched normal tissue by Southern blot hybridization with the metH probe; the tumours were also analysed for estrogen and progesterone receptors, ploidy and S phase, and protein expression of the MET and c-erbB-2 protooncogenes. PARTICIPANTS: Eighty-two patients with breast cancer. RESULTS: Fifty-three percent of the patients were informative for polymorphism with the metH marker. Somatic alterations of MET, consisting of LOH, were demonstrated in 22% of women who were informative and had breast cancer. No correlation was found between LOH of MET and conventional prognostic factors, or status for c-erbB-2 proto-oncogene expression. Estrogen-receptor status correlated with progesterone-receptor status, and S phase correlated with ploidy and size of the tumour. CONCLUSIONS: Somatic alterations of MET, detected as LOH with the metH probe, occur in 22% of informative patients. These alterations do not correlate with the prognostic factors established when the mastectomy is performed. It remains to be determined whether the patients' overall survival and disease-free survival rates are correlated with genetic alteration of MET.