Pathogenetic Dichotomy in Angioleiomyoma

Abstract

Background/Aim: Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six reported abnormal karyotypes, losses in chromosome 22 and gains in Xq found by comparative genomic hybridization, and mutation analysis of notch receptor 2 (NOTCH2), NOTCH3, platelet-derived growth factor receptor beta (PDGFRB), and mediator complex subunit 12 (MED12) in a few tumors. Herein, we report the genetic findings in another three angioleiomyomas. Materials and Methods: The tumors were examined using G-banding and karyotyping, RNA sequencing, reverse transcriptionpolymerase chain reaction, Sanger sequencing, and expression analysis. Results: The first tumor carried a t(4;5)(p12;q32) translocation resulting in fusion of the cardiac mesoderm enhancer-associated non-coding RNA (CARMN in 5q32) with the TXK tyrosine kinase gene (TXK in 4p12) leading to overexpression of TXK. To our knowledge, this is the first time that a recurrent chromosome translocation and its resulting fusion gene have been described in angioleiomyomas. The second tumor carried a four-way translocation, t(X;3;4;16)(q22;p11;q11;p13) which fused the myosin heavy chain 11 gene (MYH11 in 16p13) with intergenic sequences from Xq22 that mapped a few kilobase pairs distal to the insulin receptor substrate 4 gene (IRS4), resulting in enhanced IRS4 expression. The third angioleiomyoma carried another rearrangement of chromosome band Xq22, t(X;9)(q22;q32), as the sole cytogenetic aberration, but no material was available for further molecular investigation. Conclusion: Our data, together with previously reported abnormal karyotypes in angioleiomyomas, show the presence of two recurrent genetic pathways in this tumor type: The first is characterized by presence of the translocation t(4;5)(p12;q32), which generates a CARMN::TXK chimera. The second is recurrent rearrangement of Xq22 resulting in overexpression of IRS4.Angioleiomyoma, also known as angiomyoma, vascular leiomyoma or dermal angioma, is a benign tumor believed to arise from the smooth muscle layer (tunica media) of subcutaneous blood vessels (1). In the World Health Organization classification of soft-tissue and bone tumors, published in 2020, angioleiomyoma is considered a distinct tumor entity which, together with glomus tumor and myopericytoma, form the group of pericytic (perivascular) tumors (2). Angioleiomyoma accounts for 5% of all benign soft tumors, may occur at any age with a peak incidence between the fourth and sixth decade of life, and may arise anywhere but most frequently in the lower extremities (3). Fewer than 50 angioleiomyomas of the knee have been reported to date (4).Angioleiomyomas are typically firm, well-circumscribed nodules in which well-differentiated, perivascular smoothmuscle cells are arranged around numerous vascular channels (2). The tumor cells are consistently positive for smooth 556