MYC Is Amplified in BRCA1-Associated Breast Cancers

• Published in: Clinical cancer research 2004-01, Vol.10 (2), p.499-507
• Main Authors: GRUSHKO, Tatyana A, DIGNAM, James J, SVEEN, Lise, LYNCH, Henry T, WEBER, Barbara L, OLOPADE, Olufunmilayo I, DAS, Soma, BLACKWOOD, Anne M, PEROU, Charles M, RIDDERSTRALE, Karin K, ANDERSON, Kristin N, WEI, Min-Jie, ADAMS, April J, HAGOS, Fitsum G
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Cell Division; Disease Progression; DNA Methylation; Genes, BRCA1; Genotype; Germ-Line Mutation; Humans; In Situ Hybridization, Fluorescence; Medical sciences; Middle Aged; Multivariate Analysis; Mutation; Pharmacology. Drug treatments; Phenotype; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - metabolism; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-0976-03

Purpose: 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. Experimental Design: 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.