Article

Molecular features of the basal-like breast cancer subtype based on BRCA1 mutation status

Breast Cancer Research and Treatment (Impact Factor: 4.2). 07/2014; 147(1). DOI: 10.1007/s10549-014-3056-x
Source: PubMed

ABSTRACT BRCA1-mutated breast cancer is associated with basal-like disease; however, it is currently unclear if the presence of a BRCA1 mutation depicts a different entity within this subgroup. In this study, we compared the molecular features among basal-like tumors with and without BRCA1 mutations. Fourteen patients with BRCA1-mutated (nine germline and five somatic) tumors and basal-like disease, and 79 patients with BRCA1 non-mutated tumors and basal-like disease, were identified from the cancer genome atlas dataset. The following molecular data types were evaluated: global gene expression, selected protein and phospho-protein expression, global miRNA expression, global DNA methylation, total number of somatic mutations, TP53 and PIK3CA somatic mutations, and global DNA copy-number aberrations. For intrinsic subtype identification, we used the PAM50 subtype predictor. Within the basal-like disease, we observed minor molecular differences in terms of gene, protein, and miRNA expression, and DNA methylation variation, according to BRCA1 status (either germinal or somatic). However, there were significant differences according to average number of mutations and DNA copy-number aberrations, and four amplified regions (2q32.2, 3q29, 6p22.3, and 22q12.2), which are characteristic in high-grade serous ovarian carcinomas, were observed in both germline and somatic BRCA1-mutated breast tumors. These results suggest that minor, but potentially relevant, baseline molecular features exist among basal-like tumors according to BRCA1 status. Additional studies are needed to better clarify if BRCA1 genetic status is an independent prognostic feature, and more importantly, if BRCA1 mutation status is a predictive biomarker of benefit from DNA-damaging agents among basal-like disease.

Electronic supplementary material
The online version of this article (doi:10.1007/s10549-014-3056-x) contains supplementary material, which is available to authorized users.

Download full-text

Full-text

Available from: Judith Balmaña, Oct 14, 2014
3 Followers
 · 
108 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Triple-negative (TN) and basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormone receptors and overexpression and/or amplification of HER2. However, both classifications show substantial discordance rates when compared to each other. Here, we molecularly characterize TN tumors and BL tumors, comparing and contrasting the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 BL tumors, 21.4% and 31.5% were identified as non-BL and non-TN, respectively. TN tumors identified as luminal or HER2-enriched (HER2E) showed undistinguishable overall gene expression profiles when compared versus luminal or HER2E tumors that were not TN. Similar findings were observed within BL tumors regardless of their TN status, which suggests that molecular subtype is preserved regardless of individual marker results. Interestingly, most TN tumors identified as HER2E showed low HER2 expression and lacked HER2 amplification, despite the similar overall gene expression profiles to HER2E tumors that were clinically HER2-positive. Lastly, additional genomic classifications were examined within TN and BL cancers, most of which were highly concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based upon BL versus non-BL gene expression profiles, which appears to be the main biological difference seen in patients with TN breast cancer.
    The Oncologist 02/2013; 18(2):123-33. DOI:10.1634/theoncologist.2012-0397 · 4.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE To estimate 10-year overall survival (OS) rates for patients with early-onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive breast cancer. PATIENTS AND METHODSA total of 3,345 women with stage I to III breast cancer, age ≤ 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model. RESULTS Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75). CONCLUSION The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.
    Journal of Clinical Oncology 08/2013; 31(26). DOI:10.1200/JCO.2012.45.3571 · 18.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
    Nature 06/2011; 474(7353):609-615. DOI:10.1038/nature10166 · 42.35 Impact Factor
Show more