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.
The tumor with the 12q14-15 aberration as the sole alteration and the leiomyoma with 12q14-15 rearrangement plus deletion of the long arm of chromosome 7 were shown to express HMGIC.
In a totally benign endometrial polyp, double minute chromosomes were shown to contain an amplified and apparently nonrearranged HMGIC gene, expressed in the tumor cells, suggesting amplification of HMGIC through double minute chromosome formation as another hitherto unreported mechanism associated with the development of some mesenchymal tumors.
Some of these aberrations of chromosome 12 are not specific for particular tumor entities but can occur in a variety of tumors with HMGIC abnormalities.
The gene encoding one HMG protein, HMGI-C, is frequently rearranged or overexpressed by chromosomal translocations in common benign mesenchymal tumors including lipomas, leiomyomas, fibroadenomas, pleomorphic adenomas, aggressive angiomyxomas, and pulmonary hamartomas.
In contrast, HMGI-C expression is down-regulated during the development of the adrenal gland, completely absent in the adult individual, and only detectable in a subset of ex vivo NB tumors and in RA-resistant NB cell lines.
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.
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.
Two high-mobility group (HMG) protein genes, HMGIC and HMGIY, located at 12q15 and 6p21.3, respectively, are involved in rearrangements in various mesenchymal tumors including UL.
While a precise definition of the HMGI(Y) and HMGI-C role in tumor initiation and progression is still missing, it is likely that future investigations will contribute valuable insights to the understanding of human neoplasia.
However, HMGI-C and HMGI(Y) dysregulation as a result of specific rearrangements involving 12q15 and 6p21, the respective chromosomal sites in which the HMGI-C and HMGI(Y) genes are located, is also identified in a variety of common benign mesenchymal tumors, such as lipomas and uterine leiomyomata.
Cytogenetic aberrations involving chromosomes 6, 7, 12, and 14 constitute the major chromosomal abnormalities seen in leiomyomata and have led to the discovery that disruptions or dysregulations of HMGIC and HMGIY contribute to the development of these tumors.
From the results of the present study, it is evident that expression of HMGICcannot simply be considered a sign of neoplasia or an effect of proliferation.
Four of seven ectopic sequences previously described to be fused to exon 4 of HMGIC in different tumors were found to be located within intron 4 of the gene and thus are due to abnormal splicing.
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.
Like numerous benign mesenchymal tumors, this locally aggressive tumor is associated with rearrangements near or within HMGIC, but chimeric gene formation was not required for tumorigenesis.
Identification of these novel variants suggested that aberrant splicing can join chromosomal translocation and inversion as a mechanism for producing abnormal HMGIC transcripts, and that separation of the DNA binding domains of HMGIC from its acidic carboxyl-terminal regulatory domain can lead to development of benign mesenchymal tumors.