Gene Expression in Uterine Leiomyoma from Tumors Likely to Be Growing (from Black Women over 35) and Tumors Likely to Be Non-Growing (from White Women over 35)

<div><p>The study of uterine leiomyomata (fibroids) provides a unique opportunity to investigate the physiological and molecular determinants of hormone dependent tumor growth and spontaneous tumor regression. We conducted a longitudinal clinical study of premenopausal women with leiomyoma that showed significantly different growth rates between white and black women depending on their age. Growth rates for leiomyoma were on average much higher from older black women than for older white women, and we now report gene expression pattern differences in tumors from these two groups of study participants. Total RNA from 52 leiomyoma and 8 myometrial samples were analyzed using Affymetrix Gene Chip expression arrays. Gene expression data was first compared between all leiomyoma and normal myometrium and then between leiomyoma from older black women (age 35 or older) and from older white women. Genes that were found significant in pairwise comparisons were further analyzed for canonical pathways, networks and biological functions using the Ingenuity Pathway Analysis (IPA) software. Whereas our comparison of leiomyoma to myometrium produced a very large list of genes highly similar to numerous previous studies, distinct sets of genes and signaling pathways were identified in comparisons of older black and white women whose tumors were likely to be growing and non-growing, respectively. Key among these were genes associated with regulation of apoptosis. To our knowledge, this is the first study to compare two groups of tumors that are likely to have different growth rates in order to reveal molecular signals likely to be influential in tumor growth.</p></div

Network analysis of growing tumors compared to non-growing tumors – EGFR hub.

<p>Symbols in the figure represent the following: <b>Rectangle:</b> Nuclear receptor. <b>Oval:</b> Transcription regulator <b>Triangle:</b> Phosphatase. <b>Horizontal diamond:</b> Peptidase <b>Vertical diamond:</b> Enzyme. <b>Trapezium:</b> Transporter <b>Square with solid boundary:</b> Cytokine. <b>Square with dashed boundary:</b> Growth factor <b>Circle:</b> Other. <b>Solid line:</b> Direct interaction <b>Dashed line:</b> Indirect interaction. <b>Arrow:</b> Acts on <b>Horizontal “T”:</b> Inhibits.</p

Distribution of the number of genes as downstream targets (DSTs) of transcript-regulators.

<p>The x-axis is the # of genes as DSTs and the y-axis is the count. The table inset is a summary of the frequency distribution for the count of the DSTs (two or more) per TR.</p

Top 25 significantly down-regulated genes in uterine leiomyoma from older black women compared to older white women.

<p>Top 25 significantly down-regulated genes in uterine leiomyoma from older black women compared to older white women.</p

Top fifteen statistically significant canonical pathways identified in Leiomyoma compared to myometrium using the Ingenuity Pathway Analysis.

<p>Top fifteen statistically significant canonical pathways identified in Leiomyoma compared to myometrium using the Ingenuity Pathway Analysis.</p

Total samples collected from the FGS study for microarray analysis.

<p>Other =  Unknown (Neither white nor black).</p

Network analysis of growing tumors compared to non-growing tumors – VHL hub.

<p>Symbols in the figure represent the following: <b>Rectangle:</b> Nuclear receptor. <b>Oval:</b> Transcription regulator <b>Triangle:</b> Phosphatase. <b>Horizontal diamond:</b> Peptidase <b>Vertical diamond</b>: Enzyme. <b>Trapezium:</b> Transporter <b>Square with solid boundary:</b> Cytokine. <b>Square with dashed boundary:</b> Growth factor <b>Circle:</b> Other. <b>Solid line:</b> Direct interaction <b>Dashed line:</b> Indirect interaction. <b>Arrow:</b> Acts on <b>Horizontal “T”:</b> Inhibits.</p

Network analysis of leiomyoma compared to myometrium – ERBB2 hub.

<p>Symbols in the figure represent the following: <b>Rectangle:</b> Nuclear receptor. <b>Oval:</b> Transcription regulator <b>Triangle:</b> Phosphatas. <b>Horizontal diamond:</b> Peptidase Vertical diamond: Enzyme. <b>Trapezium:</b> Transporter <b>Square with solid boundary:</b> Cytokine. <b>Square with dashed boundary:</b> Growth factor <b>Circle:</b> Other. <b>Solid line:</b> Direct interaction <b>Dashed line:</b> Indirect interaction. <b>Arrow:</b> Acts on <b>Horizontal “T”:</b> Inhibits.</p

Manhattan plot displaying distribution of TReQTLs.

<p>The x-axis is the relative position of the SNPs across the genome in Mb. The chromosomes are illustrated by alternating shaded and unshaded sections of the plot. The order of the chromosomes is from #1 to #22 from left to right. The y-axis represents the –log₁₀<i>p</i>-value of the SNP association with the gene expression of DSTs of the TRs. <i>p</i>-values of SNPs from CEU are denoted as red circles, <i>p</i>-values of SNPs from YRI are denoted as green triangles. For visualization purposes, only SNPs having a <i>p</i>-value<0.002 in any of the 333 TRs are plotted.</p

TReQTL Gene Ontology (GO) biological process subtrees.

<p>A) Based on the GO biological processes from the gene that the YRI TReQTL SNP rs12258754 map to and those of the DSTs of activating transcription factor 3 (Atf3) and of Atf3 itself. B) Based on the GO biological processes from the gene that the CEU TReQTL SNP rs10976413 map to and those of the DSTs of miRNAs hsa-mir-181b-1 (MI0000270) and hsa-mir-181b-2 (MI0000683).</p