Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis

Abstract

Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, have recurrent cytogenetic abnormalities including del(7)(q22q32). To develop a molecular signature, matched del(7q) and non-del(7q) tumors identified by FISH or karyotyping from 11 women were profiled with expression arrays. Our analysis using paired t-tests demonstrates this matched design is critical to eliminate confounding effects of genotype and environment that underlie patient variation. A gene list ordered by genome-wide significance showed enrichment for the 7q22 target region. Modification of the gene list by weighting each sample for percent of del(7q) cells to account for the mosaic nature of these tumors further enhanced the frequency of 7q22 genes. Pathway analysis revealed two of the 19 significant functional networks were associated with development and the most represented pathway was protein ubiquitination, which can influence tumor development by stabilizing oncoproteins and destabilizing tumor suppressor proteins. Array CGH (aCGH) studies determined the only consistent genomic imbalance was deletion of 9.5 megabases from 7q22-7q31.1. Combining the aCGH data with the del(7q) UL mosacism-weighted expression analysis resulted in a list of genes that are commonly deleted and whose copy number is correlated with significantly decreased expression. These genes include the proliferation inhibitor HPB1, the loss of expression of which has been associated with invasive breast cancer, as well as the mitosis integrity-maintenance tumor suppressor RINT1. This study provides a molecular signature of the del(7q) UL subgroup and will serve as a platform for future studies of tumor pathogenesis.

miR-93/106b and Their Host Gene, MCM7, Are Differentially Expressed in Leiomyomas and Functionally Target F3 and IL-8

“…In addition to F3 and IL8 through data mining, we identified a significant number of other genes as possible direct and indirect targets of miR-106bϳ25 in TF324 cells, also expressed in leiomyomas with and without del7q22 (16). These results further illustrated the potential consequence of chromosomal rearrangements, such as del7q22, not only on the expression of many genes located at these regions but also their downstream target genes with functional association with cell cycle progression, apoptosis, inflammation, angiogenesis, and tissue turnover, influencing the outcome of leiomyoma pathogenesis.…”

“…Based on 1.5-fold change cutoff, the expression of 992 genes, including F3 and IL8, were either directly and/or indirectly altered by miR-106bϳ25 trsnsduction of which the expression of 661 gene was down-regulated and 331 genes were up-regulated as compared with untreated control (Supplemental Table 1). Through data mining we assessed whether the expression of these 992 genes are altered in del(7q) and non-del(7q) leiomyomas using the data sets reported by Hodge et al (16). The analysis identified 226 of the 992 genes as differentially expressed (P Ͻ 0.05 cutoff) in matched del(7q) and nondel(7q) leiomyomas and in TF324 cells transuding miR-106bϳ25 cluster ( Fig.…”

“…C, Treeview analysis of 226 genes differentially expressed in TF324 after miR-106ϳ25 transduction (ϩDox 6d) and untreated control (Ctrl, ϪDox) and the pattern of same genes derived from del(7q) and none-del(7q) leiomyomas (LYO-ND and LYO-DL, respectively) and myometrium (MYO). Each column represents the mean expression values from 11 matched tissues as described by Hodge et al (16).…”

“…Leiomyomas are common benign uterine tumors that develop during the reproductive years with estimated 20 -40% of the tumors characterized by chromosomal abnormalities, including 7q22 deletion (9 -11). Although the identity of factors that mediate the development of leiomyomas remain elusive, conventional and array-based studies have identified a number of candidate genes, including a few genes residing in rearranged chromosomal regions, for their potential contribution to genesis of leiomyoma (12)(13)(14)(15)(16).…”

Tissue-Specific Stem Cells in the Myometrium and Tumor-Initiating Cells in Leiomyoma1

“…However, the myometrial cell population that gives rise to these tumors has not been identified [6,7]. Several recurrent genetic aberrations, such as chromosome 12 trisomy, deletions in 7q, and mutations in genes encoding mediator complex subunit 12 (MED12) or high mobility group AT-hook 2 (HMGA2) have been reported in leiomyomas [8][9][10][11]. As in other diseases, these genetic abnormalities occurring in tumor stem cells are thought to play pivotal roles in the tumorigenesis of leiomyomas.…”