22 GENES FROM CHROMOSOME-17Q21 - CLONING, SEQUENCING, AND CHARACTERIZATION OF MUTATIONS IN BREAST-CANCER FAMILIES AND TUMORS

In our effort to identify BRCA1, 22 genes were cloned from a 1-Mb regi on of chromosome 17q21 defined by meiotic recombinants in families wit h inherited breast and/or ovarian cancer. Subsequent discovery of anot her meiotic recombinant narrowed the region to similar to 650 kb. Gene s were cloned from fibroblast and ovarian cDNA libraries by direct scr eening with YACs and cosmids, The more than 400 cDNA clones so identif ied were mapped to cosmids, YACs, and P1 clones and to a chromosome 17 somatic panel informative for the BRCA1 region, Clones that mapped ba ck to the region were hybridized to each other and consolidated into c lusters reflecting 22 genes. Ten genes were known human genes, 5 were human homologs of known genes, and 7 were novel. Each gene was sequenc ed, compared to genes in the databases to find homologies, and analyze d for mutations in BRCA1-linked families and tumors. Eight mutations w ere found in tumors or families and not in controls. In the gene encod ing alpha-N-acetylglucosaminidase, similar to 100 kb proximal to the 6 50-kb linked region, somatic nonsense, missense, and splice junction m utations occurred in 3 breast tumors, but not in these patients' germl ine DNA nor in controls. In an ets-related oncogene in the linked regi on, a missense mutation cosegregated with breast cancer in one family and was not observed in controls. In a human homolog of a yeast pre-mR NA splicing factor, 3 different mutations cosegregated with breast can cer in 3 families and were not observed in controls. In these and the other genes in the region, 36 polymorphic variants were observed in bo th cases and controls, (C) 1995 Academic Press, Inc.