7q deletion mapping and expression profiling in uterine fibroids

Abstract

Uterine fibroids are some of the most common tumours of females, but relatively little is known about their molecular basis. Several studies have suggested that deletions on chromosome 7q could have a role in fibroid formation. We analysed 165 sporadic uterine fibroids to define a small 3.2 megabase (Mb) commonly deleted region on 7q22.3-q31.1, flanked by clones AC005070 and AC007567. We also used oligonucleotide microarrays to compare the expression profiles of 10 samples of normal myometrium and 15 fibroids, nine of which displayed 7q-deletions. Activating transcription factor 3, patched homolog (Drosophila), homeo box A5, death-associated protein kinase 1, and retinoic acid receptor responder 3 were downregulated, and excision repair crosscomplementing 3, transcription factor AP-2 gamma and protein kinase C beta 1 were upregulated in fibroids. New pathways were discovered related to fibroid formation. The presence or absence of 7q-deletions did not dramatically affect the global expression pattern of the tumours; changes, however, were observed in genes related to vesicular transport and nucleic acid binding.

Fibroid-Associated Heavy Menstrual Bleeding: Correlation Between Clinical Features, Doppler Ultrasound Assessment of Vasculature, and Tissue Gene Expression Profiles

“…Of the 19 genes that we identified as significantly different between F and DM, most have been linked to F pathophysiology previously, and at least 7 (tyrosine kinase [TEK], thrombospondin 1 [THBS1], ephrin type-B receptor 4 [EPHB4], THBS2, MMP9, MMP2, and PGF) have been reported with the same direction of up-or downregulation between F and myometrium in previous array studies [13][14][15][16][17][18][19][20] This degree of concurrence with the existing literature provides considerable assurance over the validity of our findings. We showed THBS1 was down in Fs compared to myometrium, and THBS2 was up.…”

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

“…Leiomyomas frequently harbor recurrent deletions affecting 7q22, 22q, and 1p, suggesting that these regions contain tumor suppressor genes (8)(9)(10)(11). High-throughput sequencing studies have rarely detected second hit mutations within these regions, however (3,4,13), suggesting that the target genes may act in a haploinsufficient manner.…”

“…Previous expression profiling studies have discovered that hundreds of genes are differentially expressed between leiomyomas and normal myometrial tissue (9,(14)(15)(16)(17)(18)(19)(20); however, the majority of these studies have not accounted for the genetic background of the lesions examined. Therefore, we sought to explore the transcriptional differences and similarities among 94 leiomyomas from 60 patients harboring different genetic driver alterations, including HMGA2 rearrangements, MED12 mutations, biallelic inactivation of FH, COL4A5-COL4A6…”

“…Some of these rearrangements have been reported to co-occur with MED12 mutations, suggesting that a subset of HMGA1 rearrangements are secondary events (7). Leiomyomas also may harbor recurrent deletions and rearrangements of 7q22, 22q, and 1p (8)(9)(10)(11). These deletions co-occur with other genetic alterations and may be secondary driver events, often present only in a subpopulation of tumor cells (4,7,8,(11)(12)(13).…”

Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

“…Most of the 12q15 breakpoints in leiomyomas are located 5 ¶ to the HMGA2 locus (7,8), giving rise to a nontruncated HMGA2 overexpression, and are strongly associated with large leiomyomas (9,10). Leiomyomas with and without HMGA2 expression have distinctly different gene expression profiles (11,12), indicative of the unique molecular role of HMGA2 in the tumorigenesis of uterine leiomyomas.…”