Abstract 1659: Evaluation of microRNA expression profiles and their associations with risk alleles in lymphoblastoid cell lines of familial ovarian cancer

Department of Cancer Prevention and Controls, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Carcinogenesis (Impact Factor: 5.33). 03/2012; 33(3):604-12. DOI: 10.1093/carcin/bgs008
Source: PubMed


Interindividual variations of microRNA expression are likely to influence the expression of microRNA target genes and, therefore,
contribute to phenotypic differences in humans, including cancer susceptibility. Whether microRNA expression variation has
any role in ovarian cancer development is still unknown. Here, we evaluated microRNA expression profiles in lymphoblastoid
cell lines from 74 women with familial ovarian cancer and 47 unrelated controls matched on gender and race. We found that
the cases and unrelated controls can be clustered using 95 differentially expressed microRNAs with 91% accuracy. To assess
the potential implications of microRNAs in ovarian cancer, we investigated the associations between microRNA expression and
seven ovarian cancer risk variants discovered from genome-wide association studies (GWAS), namely, rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21 and rs2363956 on 19p13. We observed 130 significant associations at a permutation level of 0.01. Compared with other risk variants, rs3814113 and rs2072590 had the greatest number of significant associations (68 and 37, respectively). Interestingly, 14 microRNAs that were associated
with ovarian cancer risk alleles belong to five microRNA clusters. The most notable cluster is the tumorigenic miR-17-92 cluster with five microRNAs, all of which are significantly associated with rs3814113. Using pathway analysis, several key biological pathways were significantly overrepresented, such as cellular response to
stress (P = 2.87 × 10−06), etc. Further characterization of significant associations between microRNAs and risk alleles could facilitate the understanding
of the functions of these GWAS discovered risk alleles in the genetic etiology of ovarian cancer.

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Available from: Leonard Medico, Apr 09, 2015
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    • "We downloaded the miRNA expression profile data GSE31801 [10] from NCBI (National Center for Biotechnology Information) GEO (Gene Expression Omnibus) ( database. "
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    ABSTRACT: miRNAs are proved to have causal roles in tumorgenesis involving various types of human cancers, but the mechanism is not clear. We aimed to explore the effect of miRNAs on the development of ovarian cancer and the underlying mechanism. The miRNA expression profile GSE31801 was downloaded from GEO (Gene Expression Omnibus) database. Firstly, the differentially expressed miRNAs were screened. Target genes of the miRNAs were collected from TargetScan, PicTar, miRanda, and DIANA-microT database, then the miRNA-miRNA co-regulating network was constructed using miRNA pairs with common regulated target genes. Next, the functional modules in the network were studied, the miRNA pairs regulated at least one modules were enriched to form the miRNA functional synergistic network (MFSN). Risk miRNA were selected in MFSN according to the topological structure. Transcript factors (TFs) in MFSN were identified, followed by the miRNA-transcript factor networks construction. Totally, 42 up- and 61 down-regulated differentially expressed miRNAs were identified, of which 68 formed 2292 miRNA pairs in the miRNA-miRNA co-regulating network. GO: 0007268 (synaptic transmission) and GO: 0019226 (transmission of nerve impulse) were the two common functions of miRNAs in MFSN, and hsa-miR-579 (36), hsa-miR-942 (31), hsa-miR-105 (31), hsa-miR-150 (34), and hsa-miR-27a* (32) were selected as the hub nodes in MFSN. In all, 17 TFs, including CREM, ERG, and CREB1 were screened as the cancer related TFs in MFSN. Other TFs, such as BIN1, FOXN3, FOXK1, FOXP2, and ESRRG with high degrees may be inhibited in ovarian cancer. MFSN gave us a new shed light on the mechanism studies in ovarian cancer.
    Journal of Ovarian Research 01/2014; 7(1):9. DOI:10.1186/1757-2215-7-9 · 2.43 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in six miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women's Circle of Health Study. Allele frequencies of most SNPs (87 %) differed significantly by race. We found a number of SNPs in miRNAs and processing genes in association with breast cancer overall or stratified by estrogen receptor (ER) status. Several associations were significantly different by race, with none of the associations being significant in both races. Using a polygenic risk score to combine the effects of multiple SNPs, we found significant associations with the score in each subgroup analysis. For ER-positive cancer, each unit increment of the risk score was associated with a 51 % increased risk in AAs (OR = 1.51, 95 % CI = 1.30-1.74, p = 3.3 × 10(-8)) and a 73 % increased risk in EAs (OR = 1.73, 95 % CI = 1.45-2.06, p = 1.4 × 10(-9)). These data show, for the first time, that miRNA-related genetic variations may underlie the etiology of breast cancer in both populations of African and European ancestries. Future studies are needed to validate our findings and to explore the underlying mechanisms.
    Breast Cancer Research and Treatment 09/2013; 141(3). DOI:10.1007/s10549-013-2698-4 · 3.94 Impact Factor
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    ABSTRACT: We investigated the previously-demonstrated association of seven genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs), including rs2072590 (HOXD-AS1), rs2665390 (TIPARP), rs10088218 and rs10098821 (8q24), rs3814113 (9p22), rs9303542 (SKAP1) and rs2363956 (ANKLE1), as risk factors of epithelial ovarian tumors (EOTs). These SNPs were genotyped in two hundred seventy three patients with EOTs and four hundred sixty four unrelated healthy females from the Polish population. We observed the lowest p values of the trend test for the 9p22 rs3814113 and 8q24 rs10098821 SNPs in patients with all subtypes of ovarian cancer (ptrend = 0.010 and ptrend = 0.014, respectively). There were also significant p values for the trend of the 9p22 rs3814113 and the 8q24 rs10098821 SNPs for serous histological subtypes of ovarian cancer (ptrend = 0.006, ptrend = 0.033, respectively). Moreover, stratification of the patients based on their histological type of cancer demonstrated, in the dominant hereditary model, a significant association of the 9p22 rs3814113 SNP with serous ovarian carcinoma OR = 0.532 (95 % CI = 0.342 - 0.827, p = 0.005, pcorr = 0.035). Despite the relatively small sample size of cases and controls, our studies confirmed some of the previously-demonstrated GWAS SNPs as genetic risk factors for EOTs.
    Pathology & Oncology Research 08/2014; 21(2). DOI:10.1007/s12253-014-9822-6 · 1.86 Impact Factor
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