HMGIC is the first gene identified in chromosomal rearrangements in uterine leiomyomata and has important implications for an understanding of benign mesenchymal proliferation and differentiation.
By fluorescence in situ hybridization (FISH) we found the chromosome 12 translocation breakpoint to be mapping within the third intron of the HMGI-C gene also harboring the breakpoints of translocations involving 12q15 seen in uterine leiomyomas, lipomas, pleomorphic adenomas, and pulmonary chondroid hamartomas.
In two pulmonary chondroid hamartomas from different patients and one uterine leiomyoma with apparently normal karyotypes, we found identical RTVL-H 3' LTRs fused as ectopic sequences to exon 3 of HMGI-C.
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.
Comparisons between HMGIC gene expression in tumor samples from 11 uterine leiomyomata and 7 normal matched myometrium or in vitro cell cultures (chorionic villi, placenta, myometrium, leiomyoma, and skin) were also performed.
Furthermore, the mechanism dysregulating HMGIY in UL with 6p21.3 and 14q23-24 rearrangements may be similar to the mechanism dysregulating HMGIC in UL characterized as t(12;14)(q15;q23-24), because of the common involvement of an HMG gene and a gene at 14q23-24.
In a uterine leiomyoma and a myxoid liposarcoma with translocations 12;14 and 12;16, the breakpoints in chromosome 12 could be localized to the HMGIC and CHOP regions, respectively.
The identification of a gene rearrangement suggests a role for HMGIC in tumorigenesis of uterine leiomyoma and suggests a possible involvement of HMGIC in mesenchymal differentiation.
HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes.
In this study, we investigated the possible involvement of RAD51LI and HMGA2 (formerly known as HMGIC) in initiation and/or progression of a huge uterine leiomyoma presenting as pseudo-Meigs' syndrome.
Moreover, detection of HMGA2 expression in myometrium and in UL without 12q15 rearrangements, tissues previously thought not to express HMGA2, suggests that HMGA2 expression is required in normal adult myometrial physiology.
These data suggest that t(12;14) breakpoints contribute to the pathogenesis of uterine leiomyoma by interrupting a complex regulation of HMGA2 and other genes embedded within and around it.
The hypothesis that TC227 is a pathogenic variant is supported by a trend towards higher HMGA2 expression in TC227 allele-positive compared with non-TC227 UL tissue as well as by absence of culpable exonic sequence variants.
Recently it has been shown that repression of HMGA2 by microRNA let-7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas.
The significant (P < 0.05) overexpression of HMGA2 also in the group of fibroids without chromosomal aberrations of the 12q14-15 region suggests a general role of HMGA2 in the development of the disease.