Evaluation of BRCA1-related molecular features and microRNAs as prognostic factors for triple negative breast cancers.
BACKGROUND
The BRCA1 gene plays a key role in triple negative breast cancers (TNBCs), in which its expression can be lost by multiple mechanisms: germinal mutation followed by deletion of the second allele; negative regulation by promoter methylation; or miRNA-mediated silencing. This study aimed to establish a correlation among the BRCA1-related molecular parameters, tumor characteristics and clinical follow-up of patients to find new prognostic factors.


METHODS
BRCA1 protein and mRNA expression was quantified in situ in the TNBCs of 69 patients. BRCA1 promoter methylation status was checked, as well as cytokeratin 5/6 expression. Maintenance of expressed BRCA1 protein interaction with BARD1 was quantified, as a marker of BRCA1 functionality, and the tumor expression profiles of 27 microRNAs were determined.


RESULTS
miR-548c-5p was emphasized as a new independent prognostic factor in TNBC. A combination of the tumoral expression of miR-548c and three other known prognostic parameters (tumor size, lymph node invasion and CK 5/6 expression status) allowed for relapse prediction by logistic regression with an area under the curve (AUC) = 0.96. BRCA1 mRNA and protein in situ expression, as well as the amount of BRCA1 ligated to BARD1 in the tumor, lacked any associations with patient outcomes, likely due to high intratumoral heterogeneity, and thus could not be used for clinical purposes.


CONCLUSIONS
In situ BRCA1-related expression parameters could be used for clinical purposes at the time of diagnosis. In contrast, miR-548c-5p showed a promising potential as a prognostic factor in TNBC.
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. meriem.boukerroucha@doct.ulg.ac.be.
Meriem
M
Boukerroucha
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. c.josse@ulg.ac.be.
Claire
C
Josse
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. sonia.elguendi@doct.ulg.ac.be.
Sonia
S
ElGuendi
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. bouchra1@ymail.com.
Bouchra
B
Boujemla
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. pfreres@student.ulg.ac.be.|Medical Oncology Department, University of Liège and CHU de Liège, Liège, Belgium. pfreres@student.ulg.ac.be.
Pierre
P
Frères
GIGA-bioinformatics platform, University of Liège, Liège, Belgium. raphael.maree@ulg.ac.be.
Raphaël
R
Marée
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. s.wenric@ulg.ac.be.|Medical Oncology Department, University of Liège and CHU de Liège, Liège, Belgium. s.wenric@ulg.ac.be.
Stephane
S
Wenric
Center of Genetics, CHU de Liège, Liège, Belgium. karin.segers@chu.ulg.ac.be.
Karin
K
Segers
Medical Oncology Department, University of Liège and CHU de Liège, Liège, Belgium. joelle.collignon@chu.ulg.ac.be.
Joelle
J
Collignon
Medical Oncology Department, University of Liège and CHU de Liège, Liège, Belgium. g.jerusalem@chu.ulg.ac.be.
Guy
G
Jerusalem
Human Genetics Unit, GIGA-Cancer Research, University of Liège, Liège, Belgium. vbours@ulg.ac.be.|Center of Genetics, CHU de Liège, Liège, Belgium. vbours@ulg.ac.be.
Vincent
V
Bours
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
D019313:BRCA1 Protein; C561887:MIRN548 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger