Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma

Abstract

Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.

Figure 1.

H&E-stained sections of classic CMN (A), mixed CMN (B), and cellular CMN (C) and CFS (D) are shown. The classic CMN consists of a moderately cellular proliferation of interlacing bundles of spindle cells whereas the cellular CMN exhibits a more densely cellular histology with increased mitotic activity. The mixed CMN contains a mixture of the two patterns. The CFS is very similar in appearance to the cellular CMN.

Figure 2.

Molecular cytogenetic analyses of CMN and CFS. A and B: Giemsa emulations are derived from DAPI-stained metaphase cells of CMN 3 (A) and CFS 3 (B). Gray and blue arrows indicate chromosome 8 and 11 homologs, respectively. CMN 3 has disomy 8 and trisomy 11; CFS 3 has tetrasomy 8 and tetrasomy 11. C and D: ETV6-region FISH for the same metaphase cells shown in A and B. The t(12;15) translocations are revealed by splitting of the centromeric (rhodamine detection is red) and telomeric (FITC detection is green) ETV6-region FISH probes. E: ETV6-region FISH in 4-μm section from CMN 3. Several nuclei in center of field show wide splitting of the centromeric (red) and telomeric (green) components of the FISH probe. F: Chromosome 8 (rhodamine is red) and 11 (FITC is green) FISH in 4-μm paraffin section from CMN 3. Several nuclei show two copies of chromosome 8 and 3 copies (trisomy) of chromosome 11.

Figure 3.

ETV6-NTRK3 RT-PCR. Fusion transcripts are seen in three of four CMNs and in each of three CFSs. dH₂O is control RT-PCR with no RNA template.

Figure 4.

Sequence analysis of ETV6-NTRK3 fusion cDNA from CMN 2. Identical fusion sequences were identified in three CMNs and three CFSs.