Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor

Abstract

Inflammatory myofibroblastic tumor (IMT) is a rare, but distinctive mesenchymal neoplasm composed of fascicles of bland myofibroblasts admixed with a prominent inflammatory component. Genetic studies of IMTs have demonstrated chromosomal abnormalities of 2p23 and rearrangement of the anaplastic lymphoma kinase (ALK) gene locus. In a subset of IMTs, the ALK C-terminal kinase domain is fused with a tropomyosin N-terminal coiled-coil domain. In the current study, fusion of ALK with the clathrin heavy chain (CTLC) gene localized to 17q23 was detected in two cases of IMT. One of these cases exhibited a 2;17 translocation in addition to other karyotypic anomalies [46,XX,t(2;17)(p23;q23),add(16)(q24)].

Figure 1.

A: ALK-11 immunostaining performed on case 1 shows granular cytoplasmic staining confined to the myofibroblastic cells. B: Representative karyotype of case 1 (arrows indicate breakpoints). C: FISH performed on a destained preparation of the metaphase cell in B with a 2p23 breakpoint spanning probe shows a signal split [der(2), arrow, der(17), arrowhead]. Bicolor FISH studies performed on cytological touch preparations of cases 1 (D, left) and 2 (D, right) with probes flanking the 2p23 breakpoint show a split of the Spectrum Orange and Spectrum Green signals in two cells each, indicating disruption of ALK. Normal FISH signals are present in the remaining morphologically smaller and rounder cells (inflammatory cells). E: Portion of agarose gel showing products of second step hemi-nested RT-PCR for CLTC-ALK for case 2. The first step used the CLTC-FWD primer with ALK-REV; the second step used the CLTC-FWD primer with the ALK-3′ primer (see Materials and Methods for primer sequences). No RNA and no R.T. controls refer to lack of RNA or lack of reverse transcriptase, respectively, in the first step. M: portion of size marker PhiX174/HaeIII. F: CLTC-ALK fusion junction sequence from case 1. The identity of all transcripts was confirmed by sequencing.