Abstract
BackgroundMicroRNAs (miRNA) are 20∼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.Methodology/Principal FindingsGlobal 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/SignificanceHigh 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.
Highlights
Ovarian carcinomas are the leading cause of death among tumors of the female reproductive tract and high grade serous carcinomas are the most aggressive subtype of ovarian carcinomas [1]
We examined the miRNA expression profiles of 328 human miRNAs in a series of ovarian serous tumors, molecularly characterized with respect to their BRCA1/2 status, focusing on high grade serous carcinomas
Clinicopathologic profiles of tumor/tissue samples The series of ovarian serous tumors has been described previously [2]. These samples were extensively characterized with respect to BRCA1 and BRCA2 status with mutational and mRNA expression analysis and, in the case of BRCA1, promoter methylation and protein expression levels were analyzed
Summary
Ovarian carcinomas are the leading cause of death among tumors of the female reproductive tract and high grade serous carcinomas are the most aggressive subtype of ovarian carcinomas [1]. High grade serous carcinomas can occur in both the familial and sporadic settings. Women with germ-line BRCA1 or BRCA2 mutation are at increased risk of developing ovarian serous carcinoma while a subset of non-familial ovarian serous carcinomas demonstrate loss of BRCA1 through either somatic mutations or promoter methylation with transcriptional silencing [2]. Though typically showing the greatest tumor burden in the ovaries, there is increasing evidence that high grade serous carcinomas originate from the epithelium of the tubal fimbriae and mullerian type epithelial inclusions of the ovary in the majority of the cases [9,10,11]. 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
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