PMID- 10862052
OWN - NLM
STAT- MEDLINE
DCOM- 20000914
LR  - 20191025
IS  - 1045-2257 (Print)
IS  - 1045-2257 (Linking)
VI  - 28
IP  - 4
DP  - 2000 Aug
TI  - Multiple copies of mutant BRCA1 and BRCA2 alleles in breast tumors from germ-line 
      mutation carriers.
PG  - 432-42
AB  - Inactivation of the BRCA1 and BRCA2 breast cancer susceptibility genes has been 
      reported to occur via a germ-line mutation of one allele and a somatic loss of 
      the remaining wild-type allele. We investigated the genetic mechanisms behind the 
      second event in breast tumors from 17 BRCA1 and eight BRCA2 germ-line mutation 
      carriers, as compared with 21 sporadic breast tumors. Microsatellite markers 
      intragenic or in close proximity to both genes were used to analyze imbalances 
      between the mutant and wild-type alleles. The actual and relative gene copy 
      numbers were scored by fluorescence in situ hybridization (FISH) analysis of 
      tumor cells using locus and centromere specific probes. All but one of the 
      informative BRCA1 and BRCA2 tumors exhibited allelic imbalance and loss of the 
      corresponding wild type allele. In contrast to sporadic tumors, however, where 
      allelic imbalance at the BRCA1 and BRCA2 loci correlated well with relative copy 
      number losses by FISH, a simple reduction to a single copy (average copy number 
      ratio 2:1) was found in only two BRCA1 (12%) and four BRCA2 (50%) tumors. The 
      majority of BRCA1 and BRCA2 tumors showed a copy number reduction (relative to 
      reference probe with ratios 4:2, 3:2, 4:3) at corresponding loci, suggesting that 
      a specific physical deletion of the wild-type BRCA gene allele has been followed 
      by a duplication of the remaining mutant allele via polyploidization. Several 
      tumors contained multiple copies of BRCA1 and BRCA2 genes without relative copy 
      number changes, implying that loss of wild-type alleles is executed by 
      alternative mechanisms such as mitotic recombination, non-disjunctional 
      chromosomal loss with or without reduplication, or by gene conversion. A 
      paradoxical relative copy number gain of the mutant allele was evident in three 
      BRCA1 tumors (18%), which could be of biological relevance if a dominant negative 
      or gain-of-function model was ascribed for certain BRCA1 mutants. Our results 
      indicate that complex genetic alterations are operational at the BRCA1 and BRCA2 
      loci in tumors from genetically predisposed individuals.
FAU - Staff, S
AU  - Staff S
AD  - Laboratory of Cancer Genetics, University of Tampere, University Hospital of 
      Tampere, Institute of Medical Technology, Tampere, Finland. ss59025@uta.fi
FAU - Nupponen, N N
AU  - Nupponen NN
FAU - Borg, A
AU  - Borg A
FAU - Isola, J J
AU  - Isola JJ
FAU - Tanner, M M
AU  - Tanner MM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genes Chromosomes Cancer
JT  - Genes, chromosomes & cancer
JID - 9007329
RN  - 0 (BRCA1 Protein)
RN  - 0 (BRCA2 Protein)
RN  - 0 (Genetic Markers)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - *Alleles
MH  - BRCA1 Protein/*genetics
MH  - BRCA2 Protein
MH  - Breast Neoplasms/*genetics
MH  - Female
MH  - Gene Dosage
MH  - *Gene Duplication
MH  - *Genetic Carrier Screening
MH  - Genetic Markers/genetics
MH  - Germ-Line Mutation/*genetics
MH  - Humans
MH  - Male
MH  - Neoplasm Proteins/*genetics
MH  - Transcription Factors/*genetics
EDAT- 2000/06/22 10:00
MHDA- 2000/09/19 11:01
CRDT- 2000/06/22 10:00
PHST- 2000/06/22 10:00 [pubmed]
PHST- 2000/09/19 11:01 [medline]
PHST- 2000/06/22 10:00 [entrez]
AID - 10.1002/1098-2264(200008)28:4<432::AID-GCC9>3.0.CO;2-J [pii]
AID - 10.1002/1098-2264(200008)28:4<432::aid-gcc9>3.0.co;2-j [doi]
PST - ppublish
SO  - Genes Chromosomes Cancer. 2000 Aug;28(4):432-42. doi: 
      10.1002/1098-2264(200008)28:4<432::aid-gcc9>3.0.co;2-j.