Mutations of the BRCA1 gene on human chromosome 17q21 confer a dramatic inherited predisposition to breast and ovarian cancer. This cancer susceptibility gene also appears to be inactivated in many sporadic breast and ovarian tumors. In collaboration with Mark Skolnick's group at the University of Utah, we have localized the BRCA1 gene to a region of less than 400 kb using microsatellite-based linkage analysis of breast and ovarian cancer kindreds. A bidirectional genomic walk with Yeast Artificial Chromosomes has been completed. These clone have been used to construct cosmid contigs and a physical map of the critical region. A P1 clone contig of the region is also near completion. We have developed a powerful new technique for cDNA isolation known as direct selection or magnetic capture to identify a series of genes from the critical region that are expressed in normal breast tissue. Partial to near full length cDNA sequences have been determined for more than a dozen such genes. Extensive single strand conformation analyses of a large series of primary sporadic breast tumors and breast cancer cell lines have ruled out approximately half of these genes as candidates for the BRCA1 gene. Further mutation screens, as well as the identification of additional candidate cDNAs is in progress. In addition, we have refined our mapping of a tumor suppressor gene in the central portion of mouse chromosome 4 that is inactivated in lung tumors from a variety of carcinogen treatments on several mouse strains. This gene may be the mouse homologue of the human MLM gene that gives rise to melanoma susceptibility. We contributed to a large collaborative effort that mapped the MLM gene to human chromosome 9p21. Homozygous deletions of this chromosomal region have been noted in several human tumor types including lung cancer.
