MYC is amplified in BRCA1-associated breast cancers.
OBJECTIVE
Germ-line mutations in the BRCA1 tumor suppressor gene predispose to early onset breast cancers with a distinct phenotype characterized by high tumor grade, aneuploidy, high proliferation rate, and estrogen receptor-negativity. The molecular mechanisms and cooperative oncogenes contributing to multistep tumor progression in cells lacking BRCA1 are not well defined. To examine whether C-MYC (MYC), a transforming oncogene associated with genetic instability, contributes to multistep tumor progression in BRCA1-associated breast cancer, we have analyzed tumors from women with hereditary BRCA1-mutated and sporadic breast cancers.


METHODS
We performed fluorescence in situ hybridization using a MYC:CEP8 assay on formalin-fixed paraffin-embedded tumor tissues from 40 women with known deleterious germ-line BRCA1 mutations and 62 sporadic cases, including 20 cases with hypermethylation of the BRCA1 gene promoter.


RESULTS
We observed a MYC:CEP8 amplification ratio >/=2 in 21 of 40 (53%) BRCA1-mutated tumors compared with 14 of 62 (23%) sporadic tumors (P = 0.003). Of the 14 sporadic cases with MYC amplification, 8 (57%) were BRCA1-methylated. In total, MYC amplification was found in a significantly higher proportion of tumors with BRCA1 dysfunction (29 of 60, 48% versus 6 of 42, 14%; P = 0.0003). In a multivariable regression model controlling for age, tumor size, and estrogen receptor status, BRCA1-mutated tumors demonstrated significantly greater mean MYC:CEP8 ratio than sporadic tumors (P = 0.02).


CONCLUSIONS
Our data indicate that MYC oncogene amplification contributes to tumor progression in BRCA1-associated breast cancers. Thus, we conclude that the aggressive histopathological features of BRCA1-associated tumors are in part due to dysregulated MYC activity.
Grushko
Tatyana A
TA
Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, Illinois 60637-1463, USA.
Dignam
James J
JJ
Das
Soma
S
Blackwood
Anne M
AM
Perou
Charles M
CM
Ridderstråle
Karin K
KK
Anderson
Kristin N
KN
Wei
Min-Jie
MJ
Adams
April J
AJ
Hagos
Fitsum G
FG
Sveen
Lise
L
Lynch
Henry T
HT
Weber
Barbara L
BL
Olopade
Olufunmilayo I
OI
D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D002455:Cell Division; D019175:DNA Methylation; D018450:Disease Progression; D019398:Genes, BRCA1; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
D016271:Proto-Oncogene Proteins c-myc