Expression of Reciprocal Fusion Transcripts of the HMGIC and LPP Genes in Parosteal Lipoma

Abstract

Parosteal lipomas are rare benign neoplasms of adipose tissue that exhibit a contiguous relationship with the periosteum. These lipomas of the bone share some histopathologic features with their commonly occurring soft tissue counterparts. The latter are well-characterized cytogenetically, primarily by rearrangements involving chromosome region 12q13–q15. In particular, translocations involving 12q13–q15 are prominent, with chromosomal region 3q27–q28 as the most frequent translocation partner. Recently, we established that the genes HMGIC at 12q15 and LPP at 3q27-28 are affected by the 3;12-translocation and demonstrated that, as a direct result, HMGIC/LPP and LPP/HMGIC fusion transcripts are expressed in soft tissue lipomas. In this study, cytogenetic and molecular analyses revealed similar findings in a parosteal lipoma. Specifically, a t(3;12)(q28;q14) was detected cytogenetically in a parosteal lipoma from a 51-year-old female and subsequently confirmed by FISH utilizing a chromosome 3 breakpoint spanning YAC probe and chromosome 12 breakpoint flanking cosmid probes. RT-PCR analysis showed expression of HMGIC/LPP and LPP/HMGIC fusion transcripts in this parosteal lipoma; nucleotide sequence analysis revealed that these transcripts are identical to those expressed in soft tissue lipomas characterized by a 3;12-translocation. These findings lend further support to a common histopathogenesis between lipomas of soft tissue and parosteal origin.

Introduction

Lipomas, benign adipose tissue tumors, are the most common tumors of mesenchymal origin in humans. Lipomas most often arise superficially in the soft tissue, but occasionally they are deep-seated [1]. Parosteal lipomas are rare deep-seated tumors comprising less than 0.5% of all lipomas. These lesions exhibit a contiguous relationship with the periosteum; approximately 50% are associated with an underlying osseous reaction [2]. Typically, there is focal cortical hyperostosis involving the underlying bone, which can vary from a small focus of cortical thickening to a large bony excrescence. Cortical erosion and osseous bowing have also been reported but are less common. Virtually any bone can be involved, but the radius and femur are the most prominent. Clinically, a parosteal lipoma presents as a slowly enlarging, often asymptomatic mass; however, loss of motor and/or sensory function as a result of the compression or stretching of a nerve by the expanding lipoma may also be seen. The etiology of parosteal lipomas is not known. Because of their intimate relationship to the bone, they are considered lipomas of bone.

During the last decade, soft tissue lipomas have been studied extensively by cytogenetic analysis. At least 60% are karyotypically abnormal, with translocations involving chromosome segment 12q13–q15 most frequent 3, 4. Nearly every chromosome has been described as a translocation partner of 12q13–q15, but chromosome 3 at bands q27–q28 is preferentially involved, representing approximately 25% of all lipomas with a 12q13–q15 rearrangement. Recently we [5], as well as others [6], identified the HMGIC gene at 12q15 to be consistently affected in lipomas and a variety of other benign mesenchymal tumor types characterized by genetic aberrations involving 12q13-q15. We subsequently identified the LPP-gene at 3q27–q28 as the preferred translocation partner gene of HMGIC [7]. HMGI-C is a member of the HMGI family of high mobility group proteins and consists of three DNA-binding domains followed by an acidic tail. The protein binds to the minor groove of the chromosomal DNA [8] and it has been suggested that it may act as an architectural factor [9] in the nuclear scaffold [10] and play a critical role in the assembly of stereoscopic transcriptional complexes in the nucleus [11]. It is of interest to note that creation of a null mutation in the HMGIC gene in mice causes aberrant growth resulting in the so-called pygmy phenotype [12] and that retrovirally induced neoplastic transformation of rat thyroid cells is suppressed by the inhibition of HMGI-C protein synthesis. As far as the translocation partner gene is concerned, the LPP gene is a member of group 3 of the relatively large LIM protein gene family 13, 14. The protein is unusually proline-rich in its amino-terminal region and has three LIM domains in its carboxy-terminal region. The function of LPP is not known but database screening revealed that the LPP-encoded protein displays some similarity to the LIM protein zyxin 15, 16, which is found in immunocytochemical studies at sites of cell adhesion [17].

In this study, the chromosomal breakpoints of the 3;12-translocation (3q27-28 and 12q14) in a parosteal lipoma of the femur of a 51-year-old female were analyzed using various technologies to evaluate, at the molecular level, the implications of this genetic aberration.