An Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomas

Abstract

BackgroundUterine Leiomyomas (ULs) are the most common benign tumours affecting women of reproductive age. ULs represent a major problem in public health, as they are the main indication for hysterectomy. Approximately 40–50% of ULs have non-random cytogenetic abnormalities, and half of ULs may have copy number alterations (CNAs). Gene expression microarrays studies have demonstrated that cell proliferation genes act in response to growth factors and steroids. However, only a few genes mapping to CNAs regions were found to be associated with ULs.MethodologyWe applied an integrative analysis using genomic and transcriptomic data to identify the pathways and molecular markers associated with ULs. Fifty-one fresh frozen specimens were evaluated by array CGH (JISTIC) and gene expression microarrays (SAM). The CONEXIC algorithm was applied to integrate the data.Principal FindingsThe integrated analysis identified the top 30 significant genes (P<0.01), which comprised genes associated with cancer, whereas the protein-protein interaction analysis indicated a strong association between FANCA and BRCA1. Functional in silico analysis revealed target molecules for drugs involved in cell proliferation, including FGFR1 and IGFBP5. Transcriptional and protein analyses showed that FGFR1 (P = 0.006 and P<0.01, respectively) and IGFBP5 (P = 0.0002 and P = 0.006, respectively) were up-regulated in the tumours when compared with the adjacent normal myometrium.ConclusionsThe integrative genomic and transcriptomic approach indicated that FGFR1 and IGFBP5 amplification, as well as the consequent up-regulation of the protein products, plays an important role in the aetiology of ULs and thus provides data for potential drug therapies development to target genes associated with cellular proliferation in ULs.

MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

“…An unsupervised hierarchical clustering analysis using gene expression data previously published by our group (Cirilo et al, 2013) revealed one cluster enriched with MED12 mutated cases, in agreement with previous reports (Mehine et al, 2013). In contrast, HMGA2 expression had no influence on the clustering analysis.…”

“…Transcriptomic data (Two-Color Human GE 4×44K Microarrays, Agilent Technologies) from 42 UL from our previous study (Cirilo et al, 2013;data Table II).…”

“…Since MED12 mutation and HMGA2 overexpression were detected in the same UL, validated or predicted microRNAs of the target HMGA2 were also investigated, as an alternative mechanism of gene regulation. In addition, based on our previous data (Cirilo et al, 2013), we explored the transcriptional differences in UL and correlated the profile with MED12 mutations and HMGA2 expression levels. At surgery, 19 patients were in the proliferative menstrual cycle phase and 22 in the secretory period.…”

Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas

“…The integration of genomic and transcriptomic analysis can be used to identify cancer-driver genes and disrupted pathways, which can be drug targetable [20]. This strategy has revealed functionally relevant drivers involved in the carcinogenic process in different tumor types, including oral carcinoma [21], ovarian cancer [22], penile carcinoma [23,24], uterine leiomyoma [25] and leiomyosarcoma [26].…”

The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

“…The FA pathway has also been shown to be upregulated in infection such as HPV -infection [41] and BRCA1 appears to be localized to the cellular component of the centrosome. cancers revealed restricted expression of FANCA and BRCA1 genes [43] and these tumors exhibit dysfunction of centrosome [44]. The FANCD2-Ub can interact with PCNA proliferating cell nuclear antigen [34,44] and BRCA2/RAD51 functionally interacts with FANCD2 complex [45,46].…”