👤 Bodil Bjerkehagen

Leiomyoma of deep soft tissue is a rare type of benign smooth muscle tumor that mostly occurs in the retroperitoneum or abdominal cavity of women, and about which very little genetic information exists. In the present study, eight leiomyomas of deep soft tissue were genetically analyzed. G-banding showed that three tumors carried rearrangements of the long arm of chromosome 12, three others had 8q rearrangements, the 7th tumor had deletion of the long arm of chromosome 7, del(7)(q22), and the 8th had aberrations of chromosome bands 3q21~23 and 11q21~22. The target genes of the 12q and 8q aberrations were HMGA2 and PLAG1, respectively. In the leiomyomas with 12q rearrangements, both HMGA2 and PLAG1 were expressed whereas in the tumors with 8q aberrations, only PLAG1 was expressed. In the cases without 12q or 8q aberrations, the expression of HMGA2 was very low and PLAG1 was expressed only in the case with del(7)(q22). All eight leiomyomas of deep soft tissue expressed MED12 but none of them had mutation in exon 2 of that gene. In two tumors with 12q rearrangements, RPSAP52 on 12q14.3 was fused with non-coding RNA (accession number XR₉₄₄₁₉₅₎ from 14q32.2 or ZFP36L1 from14q24.1. In a tumor with inv(12), exon 3 of HMGA2 was fused to a sequence in intron 1 of the CRADD gene from 12q22. The present data together with those of our two previous studies in which the fusions KAT6B-KANSL1 and EWSR1-PBX3 were described in two retroperitoneal leiomyomas carrying a t(10;17)(q22;q21) and a t(9;22)(q33;q12) translocation, respectively, show that leiomyomas of deep soft tissue are genetically heterogenous but have marked similarities to uterine leiomyomas. Show less

Retroperitoneal leiomyoma is a rare benign smooth muscle tumor almost exclusively found in women and with histopathological features similar to uterine leiomyomas. The pathogenesis of retroperitoneal leiomyoma is unclear and next to nothing is known about the cytogenetics and molecular genetics of the tumor. We present here a retroperitoneal leiomyoma with a t(9;22)(q33;q12) as the sole karyotypic aberration. The translocation resulted in an EWSR1-PBX3 fusion gene in which exon 9 of EWSR1 (nucleotide 1320 accession number NM₀₁₃₉₈₆ version 3) was in-frame fused to exon 5 of PBX3 (nucleotide 824 accession number NM₀₀₆₁₉₅ version 5). The EWSR1-PBX3 fusion transcript codes for a 529 amino acids long chimeric EWSR1-PBX3 protein which contains the N-terminal transactivation part of EWSR1 and the homeodomain of PBX3. The present study, together with our previous finding of a retroperitoneal leiomyoma with t(10;17)(q22;q21) as the sole karyotypic aberration and a KAT6B-KANSL1 fusion gene, indicates that retroperitoneal leiomyomas may be characterized by fusion genes coding for chimeric proteins. However, cytogenetic and molecular heterogeneity exists in these tumors and it is too early to tell how many and which different pathways lead to retroperitoneal leiomyomagenesis. Show less

Retroperitoneal leiomyoma is a rare type of benign smooth muscle tumor almost exclusively found in women and with histopathological features similar to uterine leiomyomas. The pathogenesis of retroperitoneal leiomyoma is unclear and next to nothing is known about the cytogenetics and molecular genetics of the tumor. Here we present the first cytogenetically analyzed retroperitoneal leiomyoma. It had a t(10;17)(q22;q21) as the sole chromosomal abnormality. Using RNA-Sequencing and the 'grep' command to search the fastq files of the sequence data we found that the translocation resulted in fusion of the genes KAT6B (10q22) with KANSL1 (17q21). RT-PCR together with direct (Sanger) sequencing verified the presence of a KAT6B-KANSL1 fusion transcript. No reciprocal KANSL1-KAT6B transcript was amplified suggesting that it was either absent or unexpressed. The KAT6B-KANSL1 fusion transcript consists of exons 1 to 3 of KAT6B and exons 11 to 15 of KANSL1, is 3667 bp long, has a 1398 bp long open reading frame, and codes for a 466 amino acid residue protein. The corresponding KAT6B-KANSL1 protein contains the NEMM domain (including the linker histone H1/H5, domain H15) of KAT6B and the PEHE domain of KANSL1. The function of the fusion protein might be regulation of transcription with an affinity for chromatin (linker histone H1/H5) and interaction with the HAT domain of KAT8 (PEHE domain). The tumor expressed HMGA2 and HMGA1 even though 12q14-15 and 6p looked normal by G-banding analysis. The tumor also expressed MED12 in the absence of exon 2 mutations. Overall, the data show that the examined retroperitoneal leiomyoma resembles a subset of uterine leiomyomas in terms of histology and genetics. Show less