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Presence of a t(12;18)(q14;q21) Chromosome Translocation and Fusion of the Genes for High-mobility Group AT-Hook 2 (HMGA2) and WNT Inhibitory Factor 1 (WIF1) in Infrapatellar Fat Pad Cells from a Patient With Hoffa’s Disease

IOANNIS PANAGOPOULOS, KRISTIN ANDERSEN, LUDMILA GORUNOVA, MARTINE EILERT-OLSEN, MARIUS LUND-IVERSEN, TRYGVE WESSEL-AAS, ISABEL LLORET, FRANCESCA MICCI and SVERRE HEIM
Cancer Genomics & Proteomics September 2022, 19 (5) 584-590; DOI: https://doi.org/10.21873/cgp.20343

Abstract

Background/Aim: Hoffa’s disease is anterior knee pain presumably stemming from inflammatory fibrous hyperplasia of the infrapatellar fat pad (Hoffa’s pad). The etiology and pathogenesis are unclear, however, and no genetic information about the disease has been published. We report the genetic findings in cells from the fat pad of a patient with Hoffa’s disease. Materials and Methods: Infrapatellar fat pad cells from a patient with Hoffa’s disease were examined using cytogenetic, RNA sequencing, reverse transcription-polymerase chain reaction, and Sanger sequencing techniques. Results: Cytogenetic examination of short-term cultured cells from the Hoffa’s pad revealed a balanced t(12;18)(q14;q21) translocation as the sole chromosomal aberration. RNA sequencing detected an out-of-frame fusion of exon 3 of the gene coding for high mobility group AT-hook 2 (HMGA2) with exon 9 of the gene coding for WNT inhibitory factor 1 (WIF1). The fusion was subsequently verified by reverse transcription-polymerase chain reaction together with Sanger sequencing. Conclusion: Our data indicate that Hoffa’s disease is a neoplastic process with acquired genetic aberrations similar to those found in many benign tumors of connective tissues. The genetic aberrations are presumably acquired by mesenchymal stem cells of the infrapatellar fat pad inducing proliferation and differentiation into adipocytes or other mature connective tissue cells.

Key Words:

In 1904, the German pathologist Albert Hoffa described an infrapatellar fat pad (later called Hoffa’s pad) positioned just underneath the kneecap (patella), behind the patellar tendon and in front of the femoral condyles and tibial plateaus in patients with knee pain (1). The normal function of Hoffa’s pad is still not known but it is probably important for normal knee kinematics (2-7). Histological examination of such infrapatellar fat pads shows a typical adipose tissue structure with mature fat cells making up most of the cell population (8-10). Infrapatellar fat pads have been shown to contain mesenchymal stem cells which, under specific culture conditions, can differentiate into different connective tissue elements such as chondrocytes, adipocytes, and osteoblasts (11-13). In Hoffa’s disease, when the patient has anterior knee pain, the infrapatellar fat pad may be enlarged and display some degree of fibro-inflammatory admixture (1, 3, 9). Whether the dominant feature of such lesions is inflammation, hyperplasia, metaplasia or neoplasia, remains unknown.

We recently analyzed cytogenetically, as well as molecularly, cells from an infrapatellar fat pad removed from a patient with Hoffa’s disease. Here we report the genetic findings characterizing that lesion.

Materials and Methods

Ethics statement. The study was approved by the Regional Ethics Committee (Regional komité for medisinsk forskningsetikk Sør-Øst, Norge, http://helseforskning.etikkom.no). All clinical information has been de-identified.

Case presentation. A 41-year-old man presented with a non-tender, hard and firm lesion at the lateral aspect of the patellar tendon which had increased in size over a period of 12 months. Knee discomfort was only mild and joint mobility was normal. The skin overlying the tumor was freely moveable upon palpation. Magnetic resonance imaging of the knee showed an expansive and ill-defined soft-tissue lesion in the infrapatellar fat pad, located just lateral and dorsal to the patellar tendon and measuring 4×4×3 cm (Figure 1). The lesion appeared heterogeneous, mainly with low T2-weighted signal and no contrast enhancement, suggesting hemosiderin deposits or fibrotic content (Figure 1A and B). Some areas showed high T2-weighted signal with no contrast enhancement, indicating cystic or myxoid components. Magnetic resonance imaging showed diffuse edema affecting Hoffa’s fat pad in its entirety and the subcutaneous tissue immediately overlying the lesion (Figure 1C). Conventional X-ray examination showed no sign of mineralization in the lesion.

Figure 1.
Figure 1.

Magnetic resonance imaging of the knee showing an expansive and ill-defined lesion in the infrapatellar fat pad consistent with Hoffa’s disease. Axial T2-weighted (A) and axial T1 postcontrast fat-suppressed (B) images demonstrated a heterogeneous lesion with areas of T2 hypointensity and no contrast enhancement, suggesting fibrotic tissue or hemosiderin deposits, and areas with T2 hyperintensity with no contrast enhancement, indicating cystic or myxoid components. C: Sagittal short tau inversion recovery image revealed diffuse edema around the lesion involving the entire Hoffa fat pad and subcutaneous tissue.

The preliminary diagnosis based on clinical and radiological findings was Hoffa’s disease in chronic phase. There were no associated findings. Biopsy of the lesion showed fibrous and myxoid tissue without any sign of malignancy. After the biopsy procedure, the patient developed increasing pain in the knee, and for both diagnostic and therapeutic purposes, the lesion was surgically excised. Macroscopically, the lesion was white with well-defined borders. The surgical specimen was egg-shaped with a smooth surface but slightly whorled on cross section. Histological examination of the 37 mm diameter lesion revealed a chondromyxoid structure. The fibrous tissue in the periphery showed nodular proliferation and fascicles of spindle cells embedded in a chondromyxoid stroma. The tumor cells had vesicular nuclei with slight variation in size and shape. Mitotic figures or necrosis were not present. Tumor cells stained positive for S-100, as would be expected given their chondroid differentiation.

G-Banding and karyotyping. A part of the resected specimen was minced with scalpels into 1-2 mm fragments and then disaggregated with collagenase II (Worthington, Freehold, NJ, USA). The resulting cells were cultured, harvested, and processed for cytogenetic examination using standard techniques (14). G-Banding chromosome staining was achieved using Wright’s stain (Sigma-Aldrich, St Louis, MO, USA) (14). Peripheral blood lymphocytes stimulated with phytohemagglutinin (PHA) for 72 h were karyotyped as a control. Metaphases were analyzed and karyograms prepared using the CytoVision computer-assisted karyotyping system (Leica Biosystems, Newcastle upon Tyne, UK). The karyotype was written according to the International System for Human Cytogenomic Nomenclature (15).

RNA sequencing. Total RNA was extracted using miRNeasy Mini Kit and QIAcube according to the manufacturer’s instructions (Qiagen, Hilden, Germany) from tissue frozen and stored at –80°C adjacent to that used for cytogenetic analysis and histological examination. The tissue was disrupted and homogenized in Qiazol Lysis Reagent (Qiagen) with 5 mm stainless steel beads and TissueLyser II (Qiagen). Subsequently, total RNA was purified using QIAcube (Qiagen). The RNA quality was evaluated with a 2100 Bioanalyzer system and RNA 6000 Nano Kit (Agilent, Santa Clara, CA, USA). One microgram of total RNA was sent to the Genomics Core Facility at the Norwegian Radium Hospital, Oslo University Hospital for high-throughput paired-end RNA sequencing. A total of 123 million reads of 101-bp length were obtained. FASTQC software was used for quality control of the raw sequence data (available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Fusion transcripts were found using FusionCatcher software (16, 17).

Reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing analyses. The primers for the genes ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1), high mobility group AT-hook 2 (HMGA2), and WNT inhibitory factor 1 (WIF1) are described in Table I. Complementary DNA (cDNA) was synthesized from 1 μg of total RNA in a 20-μl reaction volume using iScript Advanced cDNA Synthesis Kit for RT-qPCR according to the manufacturer’s instructions (Bio-Rad, Hercules, CA, USA). cDNA corresponding to 20 ng total RNA was then used as template in a 25-μl reaction volume PCR assay containing 12.5 μl Premix Ex Taq™ DNA Polymerase Hot Start Version (Takara Bio Europe/SAS, Saint-Germain-en-Laye, France) and 0.4 μM of each of the forward and reverse primers (Table I). The primer combination ABL1-91F1/ABL1-404R1 was used to amplify a 338 bp cDNA fragment from the ABL1 gene in order to check the quality of cDNA synthesis. To detect the HMGA2::WIF1 fusion transcript (see below), the primer combinations HMGA2-1012F1/WIF1-1070R1 and HMGA2-982F1/WIF1-1076R1 were used. A C-1000 Thermal cycler (Bio-Rad) was used for PCR amplifications. The cycling profile was 30 s at 94°C followed by 35 cycles of 7 s at 98°C, 30 s at 60°C, 30 s at 72°C, and a final extension step for 5 min at 72°C. Three microliters of the PCR products were stained with GelRed (Biotium, Fremont, CA, USA), analyzed by electrophoresis through 1.0% agarose gel, and photographed. Gel electrophoresis was performed using lithium borate buffer (18). The remaining PCR products were purified using the MinElute PCR Purification Kit (Qiagen) and Sanger sequenced with the dideoxy procedure using the BigDye Direct Cycle Sequencing Kit in accordance with the company’s recommendations (ThermoFisher Scientific, Waltham, MA, USA). The primers used for sequencing were the same as those used for PCR with addition of M13 forward and M13 reverse sequences at their 5′-ends. The forward primers HMGA2-1012F1 and HMGA2-982F1 contained M13 forward sequence at their 5′-end (TGTAAAACGACGGCCAGT) whereas the reverse WIF1-1070R1 and WIF1-1076R1 primers contained the M13 reverse primer sequence at their 5′-end (CAGGAAACAGCTATGACC). Sequencing was run on the Applied Biosystems SeqStudio Genetic Analyzer system (ThermoFisher Scientific). The basic local alignment search tool (BLAST) was used to compare the sequences obtained by Sanger sequencing with the NCBI reference sequences NM_003483.4 (HMGA2) and NM_007191.5 (WIF1) (19).

View this table:
Table I.

Primers used for polymerase chain reaction amplification and Sanger sequencing analyses.

Results

Cytogenetic examination of short-term cultured cells from the infrapatellar fat pad revealed a balanced t(12;18)(q14;q21) translocation as the sole chromosome aberration in all examined metaphases (Figure 2). Consequently, the karyotype of the lesion was 46,XY,t(12;18)(q14;q21)[10]. At the same time, G-banding analysis of PHA-stimulated peripheral blood cells yielded a normal 46,XY karyotype. Thus, the translocation t(12;18)(q14;q21) was an acquired cytogenetic abnormality found only in cells of the infrapatellar fat pad.

Figure 2.
Figure 2.

Cytogenetic analysis of the specimen obtained from the surgically removed Hoffa’s fat pad. The karyogram shows the t(12;18)(q14;q21) chromosomal translocation as the sole cytogenetic abnormality. Breakpoint positions are indicated by arrows.

Analysis of raw sequencing data using FusionCatcher detected a fusion of exon 3 of HMGA2 from 12q14.3 (nucleotide 1060 in the NCBI reference sequences NM_003483.4) with exon 9 of WIF1 from 12q14.3 (nucleotide 1037 in reference sequence NM_007191.5): AGCCACTGGAGAAAAACGGCCAAGAGGCAGACCTAGGAAATGG-CTGTCTGCGAGCCTGGCTGTGGTGCACATGGAACCTGCCATGA. To verify the HMGA2::WIF1 fusion transcript obtained by RNA sequencing, PCR amplifications were performed with two forward HMGA2 and two reverse WIF1 primers corresponding to sequences upstream and downstream of the putative fusion point, respectively. RT-PCR with primer combinations HMGA2-1012F1/WIF1-1070R1 and HMGA2-982F1/WIF1-1076R1 amplified 103-bp and 150-bp cDNA fragments, respectively, strongly suggesting the presence of a HMGA2::WIF1 fusion transcript (Figure 3A). Sanger sequencing of both amplified cDNA fragments showed that they were HMGA2::WIF1 fusion transcripts with a fusion point identical to that found by RNA sequencing (Figure 3B).

Figure 3.
Figure 3.

Molecular genetic examination of the specimen obtained from the surgically removed fat pad of a patients with Hoffa’s disease. A: Gel electrophoresis showing the amplified cDNA fragments obtained with reverse transcription polymerase chain reaction for high-mobility group AT-hook 2 (HMGA2) and WNT-inhibitory factor 1 (WIF1) genes using the primer combinations HMGA2-1012F1/WIF1-1070R1 (L1), HMGA2-982F1/WIF1-1076R1 (L2), and ABL1-91F1/ABL1-404R1 (L3). M: GeneRuler 1 kb Plus DNA ladder (ThermoFisher Scientific). B: Partial sequence chromatograms of the cDNA amplified fragment showing the junction position of HMGA2 and WIF1 (vertical dotted line). C: The coding part of the HMGA2::WIF1 fusion transcript and the putative 124 amino acid-long HMGA2 peptide containing amino acid residues 1-82 from HMGA2 (accession number NP_003474.1) corresponding to exons 1-3 of that gene, and 42 amino acid residues from the WIF1 sequence. The 42 amino acid sequence does not correspond to any known protein nor does it have known motifs and domains. The three AT-hook domains of HMGA2 are shown in bold red letters.

The fusion transcript is predicted to be out-of-frame coding for a 124 amino acid-long protein composed of the first 82 amino acids of HMGA2 and 42 amino acids encoded by the WIF1 sequence (Figure 2C). The 42 amino acids of the latter do not correspond to any known protein, nor do they contain known motifs or domains.

Discussion

Our data strongly indicate that Hoffa’s disease – or rather the knee lesion known as Hoffa’s fat pad – is a neoplastic process. Central to this conclusion was the finding of a clonal chromosomal translocation, t(12;18)(q14;q21), as an acquired cytogenetic aberration in Hoffa’s pad cells (whereas analysis of PHA-stimulated peripheral blood cells yielded a normal 46,XY karyotype). With very few exceptions, for example trisomy 7 in solid tissue lesions (20), the general rule is that whenever acquired clonal chromosomal abnormalities are found in an investigated disease process, this means that the disease is neoplastic (21). Furthermore, but equally important, a similar t(12;18)(q14~15;q12~21) translocation has been reported before as the sole karyotypic aberration in lipomas (22).

Secondly, the detection of an HMGA2::WIF1 fusion transcript in cells cultured from the lesion strongly supports the conclusion that Hoffa’s disease is a neoplastic one, or at least that was so in the patient we examined, the only analysis of a Hoffa’s pad we have ever undertaken. An HMGA2::WIF1 fusion transcript was also reported in salivary gland pleomorphic adenomas (23-26), in a breast adenomyoepithelioma (27), and in a pleomorphic adenoma of the breast (28). In other words, HMGA2::WIF1 fusion transcripts are associated with neoplastic processes, more specifically with benign tumors. Various alternative HMGA2::WIF1 chimeric transcripts have been reported, and the transcript found in a pleomorphic adenoma of the salivary gland was identical to the transcript we describe here, i.e. it had fusion of exon 3 from HMGA2 with exon 9 from WIF1 [sequence with accession number EU263622, case 6 in (24)].

Both the HMGA2 and WIF1 genes map to chromosome subband 12q14.3. The genomic distance between them is 0.7 Mbp but they are transcribed in opposite directions. Thus, we surmise that a submicroscopic inversion occurred together with the 12q14;18q21-translocation generating the observed HMGA2::WIF1 fusion gene. The situation would be similar to what was found in a lipoma carrying a t(12;18)(q14~q15;q12~q21) together with a fusion of HMGA2 with the glutamate receptor interacting protein 1 (GRIP1) gene (22). GRIP1 also maps to chromosome subband 12q14.3 and is transcribed in the opposite direction from HMGA2.

The consequence of the HMGA2::WIF1 fusion we describe is similar to that of many other HMGA2 rearrangements found in various benign connective tissue tumors and discussed in several previous publications (22, 29-31). In brief, the 3′-untranslated region of HMGA2 (3′-UTR) strongly represses the expression of HMGA2 (32). The 3′-UTR of HMGA2 contains many regulatory elements (33), seven or eight of which target sites for the miRNA let-7 that suppresses HMGA2 expression in normal nonembryonic tissues (34, 35). Disruption of the HMGA2 locus separates exons 1-3 (or exons 1-4) from the 3′-UTR. As a consequence, the part of HMGA2 which codes for the three AT-hook binding domains (exons 1-3) becomes overexpressed and thus acts to transform the cell neoplastically. This transforming potential of truncated HMGA2 in the development of neoplasias has been repeatedly demonstrated (36-42).

In conclusion, our data indicate that the abnormal fat pad of Hoffa’s disease is not a simple inflammatory fibrous hyperplasia of infrapatellar fat cells but rather a neoplasm with acquired genetic aberrations similar to those found in many benign tumors. The genetic aberrations probably occur in mesenchymal stem cells of the infrapatellar fat pad and may induce proliferation and differentiation into adipocytes as well as other connective tissue cells, including chondrocytes and osteoblasts.

Acknowledgements

This work was supported by grants from Radiumhospitalets Legater.

Footnotes

  • Authors’ Contributions

    IP designed and supervised the research, performed molecular genetic experiments and bioinformatics analysis, and wrote the article. KA performed molecular genetic experiments and evaluated the data. LG performed cytogenetic analysis. ME-O evaluated the cytogenetic results. ML-I performed the pathological examination. TW-A made the diagnosis and surgically removed the lesion. IL performed the radiological examination. FM evaluated the data. SH assisted with experimental design and writing of the article. All Authors read and approved the final article.

  • Conflicts of Interest

    The Authors declare that they have no potential conflicts of interest.

  • Received May 3, 2022.
  • Revision received May 28, 2022.
  • Accepted June 5, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Presence of a t(12;18)(q14;q21) Chromosome Translocation and Fusion of the Genes for High-mobility Group AT-Hook 2 (HMGA2) and WNT Inhibitory Factor 1 (WIF1) in Infrapatellar Fat Pad Cells from a Patient With Hoffa’s Disease
IOANNIS PANAGOPOULOS, KRISTIN ANDERSEN, LUDMILA GORUNOVA, MARTINE EILERT-OLSEN, MARIUS LUND-IVERSEN, TRYGVE WESSEL-AAS, ISABEL LLORET, FRANCESCA MICCI, SVERRE HEIM
Cancer Genomics & Proteomics Sep 2022, 19 (5) 584-590; DOI: 10.21873/cgp.20343
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