The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4

Abstract

Subungual exostosis is a benign bone-and cartilage-forming tumor known to harbor a pathognomonic t(X;6)(q22;q13-14). Using global gene expression analysis and quantitative real-time PCR, we could show that this translocation results in increased expression of the IRS4 gene, presumably due to disruption and/or exchange of regulatory sequences with the translocation partner, the COL12A1 gene. A corresponding deregulation at the protein level could be demonstrated in primary cell cultures using a combination of fluorescence in situ hybridization and immunostaining. As the t(X;6) usually is the sole cytogenetic aberration in subungual exostosis, the deregulated expression of IRS4 is likely to be pathogenetically essential. The exact role of IRS4 is still poorly investigated, but IRS proteins are known to act as mediators of signaling from receptors, such as the insulin and insulin-like growth factor 1 receptors, and thus have an important effect on cell growth and survival.The molecular genetic characterization of balanced chromosome aberrations, in particular reciprocal translocations, has provided valuable information on the pathogenesis of a variety of neoplasms.1 Among primary bone tumors, relatively few recurrent balanced chromosome aberrations have been identified so far, and only for 2 tumor types-the Ewing family of tumors and aneurysmal bone cyst-have the molecular consequences been revealed. 2 We and others have previously shown that subungual exostoses (also known as Dupuytren's subungual exostoses) are characterized by a seemingly pathognomonic translocation t(X;6)(q22;q13-14), 3-5 but the molecular outcome of this translocation has not been identified.Subungual exostosis is a distinct, benign, bone-and cartilage-producing tumor affecting the dorsomedial aspect of the distal phalanges of the fingers and toes. It starts as a growth of cellular fibrous tissue, which subsequently undergoes enchondral ossification; the mature lesion consists of a core of trabecular bone, surrounded by a fibrocartilaginous cap. A comprehensive review by Davis and Cohen of >300 reported cases of subungual exostosis showed that the large majority (80%) of the tumors were located on the distal phalanx of the first toe, that females were more often affected (65% of the cases), and that the median age at diagnosis was 20 years, with at least 15% being children. 7 Many hypotheses concerning the etiology of the tumor have been suggested, with trauma being the most favored one. With the demonstration of a consistent translocation t(X;6) it seems safe, however, to conclude that subungual exostosis is a true neoplasm. The main differential diagnostic entities are osteochondroma, which, however, rarely arises on the digits, and bizarre parosteal osteochondromatous proliferation (BPOP, also known as Nora lesion), which more commonly develops on the proximal and middle phalanges of the fingers and toes. 4 We have previously studied a series of subungual exostoses by fluorescence in situ hybridization (FISH) and could show that the breakpo...

IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation

“…In fact, the inference that IRS4 is a constitutive active IRS is also in line with our finding that the Irs4 gene is a target for retroviral insertional mutagenesis, as this process leads with few exceptions to transcriptional deregulation of the target genes rather than to mutations affecting protein function34. The notion that IRS4 is a constitutive active oncogenic protein primarily regulated transcriptionally also explains the recent observations that chromosomal translocation events can activate Irs4 expression, leading to T-cell acute lymphoblastic leukaemia3536 and subungual exostosis (a benign bone and cartilage producing tumour)37. In addition, in human hepatocellular carcinomas (HCC), IRS4 expression is frequently upregulated compared with hepatocytes38, and its role in this malignancy has been further substantiated in the HEPG2 hepatoblastoma cell line where IRS4 plays an important role in cell proliferation39.…”

Simultaneous Translocation of Both TCR Loci (14q11) with Rare Partner Loci (Xq22 and 12p13) in a Case of T-lymphoblastic Leukemia

“…The exact role of IRS4 remains unclear; however, IRS proteins mediate signaling from insulin and insulin-like growth factor 1 receptors, and have important effects on cell growth and survival [15]. …”

Subungual Exostosis of the Toes: A Systematic Review

“…There is debate whether subungual osteochondroma is the same clinical entity as subungual exostosis. Histologically, the cartilaginous cap of exostoses is made of fibrocartilage, whereas in osteochondromas, it is hyaline cartilage and is confluent with the underlying trabecular and cortical bone [16,25] (Fig. 2).…”

“…The role of nonoperative management is limited because the condition is generally progressive. The mainstay of treatment has been marginal surgical excision of the exostosis, which typically alleviates the symptoms [25][26][27]. However, surgical techniques have varied [2,11,17,33], and the most recent literature review on this topic was published by Davis and Cohen in 1996 [8].…”