HMGIC, a high-mobility-group protein gene encoding an architectural transcription factor, was recently identified as the target of gene fusion in a variety of human benign mesenchymal tumors; some of these events were chromosomal translocations involving 12q13-15.
HMGA2 was found expressed at high levels in most samples analyzed, with clear cell carcinomas as the only exception. let-7a and miR-30c were highly deregulated in all tumor types.
HMGA2 overexpression in ULM is not only related to tumor development but also plays a role in controlling cellular proliferation through the AKT pathway.
A significant difference was found in the HMGA2 expression levels between the different grading groups (one-way ANOVA, P = 0.04) and among the fusion-negative and -positive tumors (t-test, P = 0.05), indicating that the expression level of HMGA2 was closely linked to grading, the presence/absence of the CRTC1-MAML2 fusion, and the tumor behavior of MECs.
Accordingly, by quantitative real-time PCR uterine leiomyomas with rearrangements of the HMGA2 locus were found to express significantly higher levels of FGF2 than those with an apparently normal karyotype with a linear relationship between the expression of FGF2 and the level of HMGA2 overexpression as well as the tumor size.
Akin to the HMGI-C rearrangements observed in benign solid tumors with 12q14-15 abnormalities, the HMGI(Y) gene has been assumed to play a crucial role in tumors with 6p21 abnormalities.
Amplification analysis of other genes at 12q13 (GLI, CHOP, HMGI-C and MDM2) in these 6 cases supports the view that CDK4 and MDM2 are independent targets for amplification, with variable amplification of the intervening region containing HMGI-C. Of 46 patients studied for both INK4A alterations and CDK4 amplification, the tumors in 22% contained one or the other.
Analysis of individual HMGA2 exons showed that the expression of exons 3-5 were substantially reduced when compared with exons 1-2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification.
Analysis of one tumor by 3' rapid amplification of cDNA ends showed altered transcripts in which either exons 1-3 of HMGA2 were aberrantly spliced to cryptic sites in chromosome 12 or transcripts encompassing the full coding sequence of HMGA2 through a portion of the 3' untranslated region were fused to sequence from chromosome 14.
By FISH with cosmids spanning the gene encoding the high-mobility-group protein HMGIC, we were able to show a rearrangement within or close to HMGIC in all tumors with 12q14-15 abnormalities tested, in 11 tumors with an apparently normal karyotype, and in 4 tumors with complex abnormalities without cytogenetically visible alterations of chromosomes 12.