Document Detail


Classification of IVS1-10T-->C as a polymorphism of BRCA1.
MedLine Citation:
PMID:  10459348     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations inactivating the tumor suppressor gene BRCA1 may be responsible for disease for up to 80% of familial ovarian cancer cases. In this syndrome, tumorigenesis classically initiates from an inherited mutation in one allele followed by somatic deletion of the normal allele. Sequencing of BRCA1 amplified from genomic DNA of lymphocytes and microdissected ovarian tumor cells of a familial ovarian cancer patient revealed three, rare heterozygous DNA variations (2418delA, 233G-->A, and IVS1-10T-->C) in both tumor and constitutional (lymphocyte) DNA. Thus, both copies of BRCA1 were retained in tumor. Haplotype analysis of the patient and four siblings assigned 2418delA to one copy of BRCA1 and 233G-->A and IVS1-10T-->C to the other. The DNA change, 2418delA, is considered a mutation that inactivated one BRCA1 allele because it caused a frameshift and generation of a premature stop codon, resulting in synthesis of a truncated peptide as evidenced by an in vitro protein truncation test. The DNA variation, 233G-->A, does not result in an amino acid change, and is considered a benign polymorphism. IVS1-10T-->C is a unique BRCA1 change that occurs in the last nucleotide of a consensus sequence for a branch site critical for RNA splicing. Therefore, we investigated whether IVS1-10T-->C deleteriously affected BRCA1 splicing or expression, and thereby inactivated the other BRCA1 allele. Using the technique of reverse transcription-polymerase chain reaction (PCR) with RNA isolated from lymphoid cell lines of the patient and of controls, no evidence was found that IVS1-10TC abnormally disrupted mRNA splicing or caused the absence of BRCA1 mRNA. Thus, IVS1-10T-->C is not harmful to BRCA1 function, and is classified a benign polymorphism. Retention of the normal BRCA1 allele in the tumor with the heterozygous germline BRCA1 mutation, 2418delA, indicated that mutational inactivation of both BRCA1 alleles was not required for tumorigenesis. It is possible that the normal allele may be functionally inactivated by a nonmutational mechanism.
Authors:
S Fetzer; H A Tworek; M S Piver; R A DiCioccio
Related Documents :
18471438 - Nfbd1/mdc1 stabilizes oncogenic mdm2 to contribute to cell fate determination in respon...
20798688 - A positive role for c-abl in atm and atr activation in dna damage response.
8242748 - Differential induction of transcriptionally active p53 following uv or ionizing radiati...
19918068 - Dual inactivation of hus1 and p53 in the mouse mammary gland results in accumulation of...
24497308 - Chiral discrimination of ofloxacin enantiomers using dna double helix regulated by meta...
2052018 - A plasmodium falciparum-specific reverse target capture assay.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer genetics and cytogenetics     Volume:  113     ISSN:  0165-4608     ISO Abbreviation:  Cancer Genet. Cytogenet.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-09-10     Completed Date:  1999-09-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7909240     Medline TA:  Cancer Genet Cytogenet     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  58-64     Citation Subset:  IM    
Affiliation:
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, NY 14263, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
BRCA1 Protein / genetics*
Base Sequence
Breast Neoplasms / genetics
DNA, Complementary / analysis
Exons
Female
Haplotypes
Humans
Introns
Lymphocytes / metabolism
Male
Molecular Sequence Data
Ovarian Neoplasms / genetics
Pedigree
Polymorphism, Genetic*
Polymorphism, Single-Stranded Conformational
RNA, Messenger / analysis
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
CA 16056/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/BRCA1 Protein; 0/DNA, Complementary; 0/RNA, Messenger

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Cytogenetic divergence of the same blastic clone in transformed chronic granulocytic leukemia: no ef...
Next Document:  Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas.