Deletions on chromosome 4 in sporadic and BRCA mutated tumors and association with pathological variables.
BACKGROUND
Chromosomal aberrations in breast tumors from BRCA1 and BRCA2 germ-line mutation carriers are considerably more frequent than what is seen in sporadic breast tumors. According to Comparative Genomic Hybridisation analysis (CGH), deletions on chromosome 4 are one of the most frequent events in BRCA1-associated tumors, suggesting inactivation of specific tumor suppressor genes.


METHODS
In the present study, 16 microsatellite markers covering chromosome 4 were used to map loss of heterozygosity (LOH) in tumors from BRCA1 (n=41) as well as in tumors from BRCA2 (n=66) mutation carriers and in tumors from unselected cases of breast cancer (n =68).


RESULTS
The frequency of LOH in these groups ranged from 16-73% in BRCA1-associated tumors, 13-42% in BRCA2-associated tumors and 8-33% in unselected tumors. LOH was significantly more frequent in BRCA1-associated tumors as compared to BRCA2-associated tumors and unselected tumors, and particularly high (over 70%) at 4q35.2. Pathological variables that were found significantly associated (p< or =0.05) with LOH at specific markers were: high percentage of cells in S-phase, negative estrogen receptor status, young age at diagnosis and large tumors. Deletion mapping indicates the existence of seven non-overlapping regions at chromosome 4, which were identified in all three groups of tumors. Three of these seven regions, 4p16.3-p16.1, 4q27-q32.1 and 4q35.1-4qter, have not been reported in breast cancer previously.


CONCLUSIONS
The results manifest the frequent alterations of chromosome 4 in BRCA1-associated breast tumors and indicate the location of several genes of potential importance in breast cancer development.
Johannsdottir
Hrefna K
HK
Department of Pathology, Landspitali-University Hospital by Hringbraut, Reykjavik, Iceland.
Johannesdottir
Gudrun
G
Agnarsson
Bjarni A
BA
Eerola
Hannaleena
H
Arason
Adalgeir
A
Johannsson
Oskar T H
OT
Heikkilä
Päivi
P
Egilsson
Valgardur
V
Olsson
Hakan
H
Borg
Ake
A
Nevanlinna
Heli
H
Barkardottir
Rosa B
RB
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D009693:Nucleic Acid Hybridization
D004273:DNA, Neoplasm