The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.
Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1-deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status.
Department of Oncology, CREATE Health Strategic Center for Translational Cancer Research, Lund University, Skåne Department of Oncology, Skåne University Hospital, Lund, Sweden.
Göran
G
Jönsson
Johan
J
Staaf
Johan
J
Vallon-Christersson
Markus
M
Ringnér
Sofia K
SK
Gruvberger-Saal
Lao H
LH
Saal
Karolina
K
Holm
Cecilia
C
Hegardt
Adalgeir
A
Arason
Rainer
R
Fagerholm
Camilla
C
Persson
Dorthe
D
Grabau
Ellinor
E
Johnsson
Kristina
K
Lövgren
Linda
L
Magnusson
Päivi
P
Heikkilä
Bjarni A
BA
Agnarsson
Oskar T
OT
Johannsson
Per
P
Malmström
Mårten
M
Fernö
Håkan
H
Olsson
Niklas
N
Loman
Heli
H
Nevanlinna
Rosa B
RB
Barkardottir
Åke
Å
Borg
D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D015321:Gene Rearrangement; D019398:Genes, BRCA1; D016161:Genes, Retinoblastoma; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018295:Neoplasms, Basal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016160:Retinoblastoma Protein