We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.
PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.
Genetic studies have revealed a network of three unlinked regulatory genes that control the developmental expression of the family of endogenous lectins in Dictyosteliurn discoideurn.Mutations in the disA and dis5 loci have a null phenotype and do not express the discoidin I or I I lectins. The third mutation, drsA, is a second-site suppressor of the dis5 mutation, which restores expression of all lectin species. Cells carrying this mutation express the discoidin lectins during growth, which is in contrast to wild-type cells in which lectin synthesis is developmentally regulated. In addition to this basic level of genetic control, the conditions of growth dramatically influence the patterns of discoidin expression. Growth-phase wild-type cells do not express lectin if the cells are grown on plates in association with bacteria. However, wild-type cells growing in bacterial suspensions express high levels of lectin during growth. Synthesis of the discoidin lectins in growing cells is sensitive to the levels of extracellular cyclic adenosine monophosphate (CAMP) and folic acid. These results suggest that the drsA mutation renders cells insensitive to cAMP and/or folate and thus allows expression of lectin during growth.
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