Characterization of Neoplasm-Specific Chromosomal Aberrations and Their Molecular Consequences in Lipomas: Identification of the HMGA2::LINC00535 Fusion Transcript

Abstract

Acquired genetic alterations are known to drive neoplastic transformation and tumor development. On a molecular level, chromosomal aberrations can lead to the formation of fusion transcripts, which may play a role in tumorigenesis. These aberrations and their gene products are in many cases characteristic of neoplasms and are used to subclassify tumors. They are often valuable biomarkers for diagnostic, prognostic and therapeutic purposes. The aim of this project was to increase the knowledge of chromosomal aberrations and their molecular consequences in lipomas by investigating two lipomas showing rearrangements of the 8q21-q22 and 12q14 chromosomal bands in their karyotypes. Since the breakpoints of both rearrangements map on the same chromosomal bands, it was thought that these aberrations could form the same gene products, hence this was investigated in this project.

Output from previous total RNA sequencing of the two lipomas were investigated for fusion transcripts, where the ones involving sequences from both 8q21-q22 and 12q14 chromosomal bands were of interest. Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Sanger sequencing were performed to verify these transcripts and to localize the breakpoint of the fusions more precisely. Verification of the rearrangements at the genome level was performed through Fluorescent In Situ Hybridization (FISH). Furthermore, array Comparative Genomic Hybridization (aCGH) was used as an exploratory method to screen the genomes for imbalanced cryptic aberrations and thereby gain further knowledge of chromosomal aberrations in these lipomas.

Aberrations involving the 8q22 and 12q14 chromosomal bands were found to be recurrent in lipomas and led to the formation of an HMGA2::LINC00535 fusion transcript, which has not been previously identified. If translated into a protein, a truncated High-Mobility Group AT-hook 2 (HMGA2) protein may be formed, which is already thought to play a role in the development of lipomas and other tumors. Furthermore, no imbalanced cryptic aberrations were identified in the two lipomas. Combining these findings with clinical information may contribute to distinguish benign lipomas more efficiently from malignant adipocytic tumors and thereby improve the subclassification of these tumors. This could further enhance the decision-making regarding diagnosis, prognosis and treatment of adipocytic tumors. However, further studies, involving other lipomas and adipocytic tumors, are needed to determine if the HMGA2::LINC00535 fusion transcript is specific for lipomas.