Project description:Plexiform leiomyomata are a histologically defined subgroup of benign uterine smooth muscle tumors based on their epitheliod cytology and abundant extracellular matrix. We used microarrays to compare plexiform leiomyomata to normal myometrium (smooth muscle of the uterine wall), typical leiomyomata, cellular or atypical leiomyomata and malignant leiomyosarcoma of the uterus. Keywords: tumor analysis
Project description: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. Keywords: uterine leiomyomata, fibroids, del(7)(q22q32), gene expression, aCGH, microarray
Project description:Plexiform leiomyomata are a histologically defined subgroup of benign uterine smooth muscle tumors based on their epitheliod cytology and abundant extracellular matrix. We used microarrays to compare plexiform leiomyomata to normal myometrium (smooth muscle of the uterine wall), typical leiomyomata, cellular or atypical leiomyomata and malignant leiomyosarcoma of the uterus. Experiment Overall Design: Samples analyzed on U133 Plus 2.0 and HuFL (GPL570 and GPL80). Experiment Overall Design: Data from the microarrays was merged by selection data for probe sets in which Entrez gene ID code on the GPL570 table equaled the Entrez gene ID on the GPL80 table. Experiment Overall Design: If more than one row on the GPL570 matched the value of the Entrez gene ID for a probe set on the GPL80 table, the values from the GPL570 were averaged. Thus, the GPL570 data was condensed to conform to the GPL80 format. Experiment Overall Design: The reformated raw data from both microarrays was then normalized such that the sum of the expression values was 3 million, and that values less than 20 were subsequently set to 20 (to permit log transformation in some statistical analysis).
Project description:Uterine leiomyomata (UL), the most common neoplasm in reproductive age women, have recurrent cytogenetic abnormalities including t(12;14). To develop a molecular signature, matched t(12;14) and non-t(12;14) tumors identified by FISH or karyotyping from each of 9 women were profiled using Affymetrix GeneChip U133 Plus 2.0 oligonucleotide arrays. Model analysis demonstrated the necessity for a matched design to eliminate the confounding effect of genotype and environment that underlay patient to patient variation.
Project description: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. Experiment Overall Design: Matched del(7q) and non-del(7q) tumors identified by FISH or karyotyping from each of eleven woman were profiled using Affymetrix GeneChip U133 Plus 2.0 oligonucleotide gene expression arrays.
Project description:Uterine leiomyomata (UL), the most common neoplasm in reproductive age women, have recurrent cytogenetic abnormalities including t(12;14). To develop a molecular signature, matched t(12;14) and non-t(12;14) tumors identified by FISH or karyotyping from each of 9 women were profiled using Affymetrix GeneChip U133 Plus 2.0 oligonucleotide arrays. Model analysis demonstrated the necessity for a matched design to eliminate the confounding effect of genotype and environment that underlay patient to patient variation. Matched myometrium, t(12;14) fibroid tumors and non-t(12;14) fibroid tumors identified by FISH or karyotyping from each of 9 women were profiled using Affymetrix GeneChip U133 Plus 2.0 oligonucleotide gene expression arrays.
Project description:Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on women’s health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma. Experiment Overall Design: We analyzed 1-3 leiomyoma or normal myometrium biopsies from each 23 woman undergoing hysterectomy for the treatment of uterine fibroids. tment and compared it leiomyoma and normal myometrium from the Eker rat model of uterine fibroids (N=14-15)
Project description:Adenomyosis, defined as ectopic endometrial tissue within the myometrium, can often be misdiagnosed as multiple uterine leiomyomata or endometrial thickening. We therefore performed a combined mRNA and long noncoding (lnc)RNA microarray and bioinformatic analysis of eutopic and ectopic endometrium in women with adenomyosis to better understand its pathogenesis and help in the development of a semi-invasive diagnostic test. A total of 586 mRNAs were increased and 305 mRNAs decreased in ectopic endometrium of adenomyosis compared with eutopic endometrium, while 388 lncRNA transcripts were up-regulated and 188 down-regulated in ectopic compared with paired eutopic endometrial tissue. Bioinformatic analysis suggested a series of metabolic and molecular abnormalities in adenomyosis, which have many similarities with endometriosis. Furthermore, our study constitutes the first known report of lncRNA expression patterns in human adenomyosis ectopic and eutopic endometrial tissue. Two-condition experiment, ectopic endometrium vs. eutopic endometrium. 3 samples,self-control