Population genetics of BRCA1 and BRCA2.
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BRCA2 Protein↗
Biomedical subjects
C I Szabo
Publications and source records attributed to C I Szabo.
BRCA1 is secreted and exhibits properties of a granin.
Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer. However, the function of the BRCA1 protein has remained elusive. We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones. As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products.
Amino Acid Sequence↗
Human, canine and murine BRCA1 genes: sequence comparison among species.
Five to ten percent of breast cancer in the western world may be attributed to the inheritance of highly penetrant mutations in the breast and ovarian cancer susceptibility gene, BRCA1. The biological function of BRCA1 and factors affecting expressivity, such as gene-environment and gene-gene interactions, may be more effectively studied in appropriate animal models. We report the cloning and sequencing of the canine and murine BRCA1 genes and contrast the sequences with human BRCA1. The amino terminal 120 residues of the gene are > 80% identical among the three species. The C-terminus is also highly conserved, containing an 80 amino acid stretch that is over 80% identical. Motifs of likely functional significance are maintained, including the amino terminal RING finger motif (amino acids 24-64) and the granin consensus sequence (1214-1223). The distribution of missense mutations and neutral polymorphisms identified in BRCA1-linked breast cancer suggests that disease associated missense mutations occur at highly conserved residues whereas polymorphisms are in regions of lower conservation. Among eighteen missense mutations with unknown consequences, seven occur in amino acids that are identical across species. Four of these seven (E1219D, A1708E, P1749R and M1775R) are also within conserved domains. Taken together, these data predict regions of the gene which may be critical for normal function.
Amino Acid Sequence↗
Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.
Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCA1. Loss of the wild-type allele in > 90% of tumors from patients with inherited BRCA1 mutations indicates tumor suppressive function. The low incidence of somatic mutations suggests that BRCA1 inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library. The 24 exons of BRCA1 span an 81-kb region that has an unusually high density of Alu repetitive DNA (41.5%), but relatively low density (4.8%) of other repetitive sequences. BRCA1 intron lengths range in size from 403 bp to 9.2 kb and contain the intragenic microsatellite markers D17S1323, D17S1322, and D17S855, which localize to introns 12, 19, and 20, respectively. In addition to BRCA1, the contig contains two complete genes: Rho7, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the 1A1-3B B-box protein pseudogene and IFP 35, an interferon induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The order of genes on the chromosome is: centromere-1FP 35-VAT1-Rho7-BRCA1-1A1-3B-telomere.
Breast Neoplasms↗
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 region of chromosome 17q21 defined by meiotic recombinants in families with inherited breast and/or ovarian cancer. Subsequent discovery of another meiotic recombinant narrowed the region to approximately 650 kb. Genes were cloned from fibroblast and ovarian cDNA libraries by direct screening with YACs and cosmids. The more than 400 cDNA clones so identified were mapped to cosmids, YACs, and P1 clones and to a chromosome 17 somatic panel informative for the BRCA1 region. Clones that mapped back to the region were hybridized to each other and consolidated into clusters reflecting 22 genes. Ten genes were known human genes, 5 were human homologs of known genes, and 7 were novel. Each gene was sequenced, compared to genes in the databases to find homologies, and analyzed for mutations in BRCA1-linked families and tumors. Eight mutations were found in tumors or families and not in controls. In the gene encoding alpha-N-acetylglucosaminidase, approximately 100 kb proximal to the 650-kb linked region, somatic nonsense, missense, and splice junction mutations occurred in 3 breast tumors, but not in these patients' germline DNA nor in controls. In an ets-related oncogene in the linked region, a missense mutation cosegregated with breast cancer in one family and was not observed in controls. In a human homolog of a yeast pre-mRNA splicing factor, 3 different mutations cosegregated with breast cancer in 3 families and were not observed in controls. In these and the other genes in the region, 36 polymorphic variants were observed in both cases and controls.
BRCA1 Protein↗
Inherited breast and ovarian cancer.
An estimated 5 to 10% of all breast and ovarian cancer is attributable to inherited mutations in two highly penetrant autosomal dominant susceptibility genes, BRCA1 and BRCA2. BRCA1 confers higher risk of ovarian cancer and BRCA2 much higher risk of male breast cancer. With the exception of missense mutations in the RING finger near the amino terminus of BRCA1, virtually all germline mutations in the gene cause the novel BRCA1 protein to be prematurely truncated. Approximately 90% of breast tumors in BRCA1 families, 50% of unselected breast tumors and 65-80% of unselected ovarian tumors have lost one allele of BRCA1 by somatic deletion. Very few tumors have detectable somatic point mutations in BRCA1. Inhibition of BRCA1 expression in mammary epithelial cell lines also suggests that BRCA1 may act as a tumor suppressor. The biological function of BRCA1 is still unknown, although identification of a patient homozygous for an inherited BRCA1 mutation suggests that the gene's function may be essential only to specific tissues. At least two other genes, P53 and the androgen receptor, are responsible for inherited predisposition to breast cancer in rare families. Several epidemiologic studies suggest that individuals carrying rare alleles at a minisatellite flanking the HRAS locus are at increased risk of cancer, including breast cancer. Finally, preliminary epidemiologic studies also suggest that individuals heterozygous for mutations in the ataxia telangiectasia gene may be at increased risk of breast cancer.
BRCA1 Protein↗
Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.
Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2.
Alleles↗
The search for BRCA1.
BRCA1, a gene predisposing to breast and ovarian cancer, was mapped to chromosome 17q21 by linkage analysis. Loss of heterozygosity in breast and ovarian tumors from BRCA1-linked patients always involved loss of wild-type alleles from chromosome 17q21, suggesting that BRCA1 acts as a tumor suppressor gene. Meiotic recombination in linked families constrained the BRCA1 region to an estimated physical size of 650 kilobases. Twenty-two candidate genes were isolated by screening complementary DNA libraries with yeast artificial chromosomes and cosmids from the critical region. Of these, 8 were known human genes, 7 were homologues of genes identified in other species, and 7 encoded novel transcripts. Each gene were sequenced and analyzed for variation, revealing 44 variants, including two missense mutations in two genes which segregated with breast cancer and were not found in controls. However, no frame-shift, nonsense, or regulatory mutations were found.
Base Sequence↗
Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.
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.
BRCA1 Protein↗
Green pigs, red herrings, and a golden hoe: a retrospective on the identification of BRCA1 and the beginning of its characterization.
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BRCA1 Protein↗