Gene fusions AHRR-NCOA2, NCOA2-ETV4, ETV4-AHRR, P4HA2-TBCK, and TBCK-P4HA2 resulting from the translocations t(5;8;17)(p15;q13;q21) and t(4;5)(q24;q31) in a soft tissue angiofibroma

Abstract

We present an angiofibroma of soft tissue with the karyotype 46,XY,t(4;5)(q24;q31),t(5;8;17)(p15;q13;q21)[8]/46,XY,t(1;14)(p31;q32)[2]/46,XY[3]. RNA‑sequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an in‑frame TBCK‑P4HA2 and the reciprocal but out‑of‑frame P4HA2‑TBCK fusion transcripts. The putative TBCK‑P4HA2 protein would contain the kinase, the rhodanese‑like domain, and the Tre‑2/Bub2/Cdc16 (TBC) domains of TBCK together with the P4HA2 protein which is a component of the prolyl 4‑hydroxylase. The t(5;8;17)(p15;q13;q21) three‑way chromosomal translocation targeted AHRR (on 5p15), NCOA2 (on 8q13), and ETV4 (on 17q21) generating the in‑frame fusions AHRR‑NCOA2 and NCOA2‑ETV4 as well as an out‑of‑frame ETV4‑AHRR transcript. In the AHRR‑NCOA2 protein, the C‑terminal part of AHRR is replaced by the C‑terminal part of NCOA2 which contains two activation domains. The NCOA2‑ETV4 protein would contain the helix‑loop‑helix, PAS_9 and PAS_11, CITED domains, the SRC‑1 domain of NCOA2 and the ETS DNA‑binding domain of ETV4. No fusion gene corresponding to t(1;14)(p31;q32) was found. Our findings indicate that, in spite of the recurrence of AHRR‑NCOA2 in angiofibroma of soft tissue, additional genetic events (or fusion genes) might be required for the development of this tumor.

Figure 1

Microscopic examination of the angiofibroma of soft tissue. (A) H&E-100×. (B) H&E-200×. (C) H&E-400×. (D) Immunoexpression of MIB1-200×. (E) Immunoexpression of CD34-200×.

Figure 2

Cytogenetic analysis of the angiofibroma of soft tissue. (A) Partial karyotype showing from left to right the chromosomes 4, der(4)t(4;5) (q24;q31), der(5)t(4;5)(q24;q31), der(5)t(5;8;17)(p15;q13;q21), 8, der(8)t(5;8;17) (p15;q13;q21), der(17)t(5;8;17)(p15;q13;q21), and 17. (B) Partial karyotype showing the der(1)t(1;14)(p31;q32) and der(14)t(1;14)(p31;q32) together with the corresponding normal chromosome homologs. Breakpoint positions are indicated by arrows.

Figure 3

Partial sequence chromatogram of the amplified cDNA fragment showing the junction points of the fusion transcripts. (A) P4HA2-TBCK, (B) TBCK-P4HA2, (C) exon 12 of AHRR with sequence of intron 14 of NCOA2, (D) exon 12 of AHRR with exon 14 of NCOA2, (E) ETV4-AHRR, and (F) NCOA2-ETV4.

Figure 4

Illustration of the proteins AHRR, NCOA2, AHRR-NCOA2, NCOA2-ETV4, and TBCK-P4H2A. The domains, their accession nos., and intervals are also shown. Arrows in the AHRR protein indicate the known fusion points for the published AHRR-NCOA2 proteins. Arrows in the AHRR-NCOA2, NCOA2-ETV4, and TBCK-P4H2A show the fusion points in the present angiofibroma of soft tissue.