Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors.
Comparative genomic hybridization (CGH) analysis has shown that chromosome 5q deletions are the most frequent aberration in breast tumors from BRCA1 mutation carriers. To map the location of putative 5q tumor suppressor gene(s), 26 microsatellite markers covering chromosome 5 were used in loss of heterozygosity (LOH) analysis of breast tumors from BRCA1 (n = 42) and BRCA2 mutation carriers (n = 67), as well as in sporadic cases (n = 65). High-density array CGH was also used to map chromosome 5 imbalance in 10 BRCA1 tumors. A high LOH frequency was found in BRCA1 tumors (range 19-82%), as compared to BRCA2 and sporadic tumors (ranges 11-44% and 7-43%, respectively). In all, 11 distinct chromosome 5 regions with LOH were observed, the most frequent being 5q35.3 (82%), 5q14.2 (71%) and 5q33.1 (69%) in BRCA1 tumors; 5q35.3 (44%), 5q31.3 (43%) and 5q13.3 (43%) in BRCA2 tumors and 5q31.3 (43%) in sporadic tumors. Array CGH analysis confirmed the very high frequency of 5q deletions, including candidate tumor suppressor genes such as XRCC4, RAD50, RASA1, APC and PPP2R2B. In addition, 2 distinct homozygous deletions were identified, spanning regions of 0.7-1.5 Mbp on 5q12.1 and 5q12.3-q13.1, respectively. These regions include only a few genes, most notably BRCC3/DEPDC1B (pleckstrin/G protein interacting and RhoGAP domains) and PIK3R1 (PI3 kinase P85 regulatory subunit). Significant association (p < or = 0.05) was found between LOH at certain 5q regions and factors of poor prognosis, including negative estrogen and progesterone receptor status, high grade, large tumor size and high portion of cells in S-phase. In conclusion, our results confirm a very high prevalence of chromosome 5q alterations in BRCA1 tumors, pinpointing new regions and genes that should be further investigated.
Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland.
Hrefna K
HK
Johannsdottir
Goran
G
Jonsson
Gudrun
G
Johannesdottir
Bjarni A
BA
Agnarsson
Hannaleena
H
Eerola
Adalgeir
A
Arason
Paivi
P
Heikkila
Valgardur
V
Egilsson
Hakan
H
Olsson
Oskar Th
OT
Johannsson
Heli
H
Nevanlinna
Ake
A
Borg
Rosa B
RB
Barkardottir
D000328:Adult; D000368:Aged; D022981:Allelic Imbalance; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D016133:Polymerase Chain Reaction