MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying high-grade serous carcinomas of ovary.
BACKGROUND
MicroRNAs (miRNA) are 20 approximately 25 nucleotide non-coding RNAs that inhibit the translation of targeted mRNA, and they have been implicated in the development of human malignancies. High grade serous ovarian carcinomas, the most common and lethal subtype of ovarian cancer, can occur sporadically or in the setting of BRCA1/2 syndromes. Little is known regarding the miRNA expression profiles of high grade serous carcinoma in relation to BRCA1/2 status, and compared to normal tubal epithelium, the putative tissue of origin for high grade serous carcinomas.


RESULTS
Global miRNA expression profiling was performed on a series of 33 high grade serous carcinomas, characterized with respect to BRCA1/2 status (mutation, epigenetic silencing with loss of expression or normal), and with clinical follow-up, together with 2 low grade serous carcinomas, 2 serous borderline tumors, and 3 normal fallopian tube samples, using miRNA microarrays (328 human miRNA). Unsupervised hierarchical clustering based on miRNA expression profiles showed no clear separation between the groups of carcinomas with different BRCA1/2 status. There were relatively few miRNAs that were differentially expressed between the genotypic subgroups. Comparison of 33 high grade serous carcinomas to 3 normal fallopian tube samples identified several dysregulated miRNAs (false discovery rate <5%), including miR-422b and miR-34c. Quantitative RT-PCR analysis performed on selected miRNAs confirmed the pattern of differential expression shown by microarray analysis. Prognostically, lower level miR-422b and miR-34c in high grade serous carcinomas were both associated with decreased disease-specific survival by Kaplan-Meier analysis (p<0.05).


CONCLUSIONS
High grade serous ovarian carcinomas with and without BRCA1/2 abnormalities demonstrate very similar miRNA expression profiles. High grade serous carcinomas as a group exhibit significant miRNA dysregulation in comparison to tubal epithelium and the levels of miR-34c and miR-422b appear to be prognostically important.
Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada. chenghan@interchange.ubc.ca
Cheng-Han
CH
Lee
Subbaya
S
Subramanian
Andrew H
AH
Beck
Inigo
I
Espinosa
Janine
J
Senz
Shirley X
SX
Zhu
David
D
Huntsman
Matt
M
van de Rijn
C Blake
CB
Gilks
D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000096:biosynthesis*; D024682:BRCA2 Protein / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000196:embryology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D035683:MicroRNAs