Two Fusions

A translocation that brings together the genes for TAZ (WWTR1) ahd CAMTA1 is responsible for ~90% of EHE cases while 10% involve fusion of YAP, (a paralogue, closely related gene of TAZ) with TFE3. A new paper from Korea (citation below) analyzed 18 EHE specimens and found that while all of them were positive for the TAZ-CAMTA fusion, 5 of them also had the YAP-FTE3 fusion. Note that one possible explanation for sudden conversion of dormant EHE to aggressive disease could be the occurrence of a second mutation. Could this fusion of paralogous YAP be an example of such an activating mutation. They also try to make a connection between the TFE3 fusion and clinical presentation at an earlier age with a tendency to larger, single tumor. There could be something I'm missing, but their analysis of the data and conclusions seem to me of limited practical or scientific value in terms of treating patients or having a better understanding the disease. By the way, the word, compossible used in the title was new to me, so I thank the authors for that. It means what it sounds like: two things that can exist together or, compatible.

Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements Seok Joo Lee, Woo Ick Yang, Woo-Suk Chung and Sang Kyum Kim Department of Pathology, Yonsei University Medical Center, Seoul, South Korea

ABSTRACT: Epithelioid hemangioendotheliomas (EHEs) are vascular tumors of intermediate malignancy that can undergo high-grade malignant transformations. EHEs have been characterized by tumor-specific WW domain-containing transcription regulator 1(WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) translocations, and recently, a novel Yes-associated protein 1 (YAP1)-transcription factor E3 (TFE3) gene fusion was identified in EHEs. In this study, we examined the expression levels of TFE3 and CAMTA1 via immunohistochemical staining and identified chromosomal alterations using fluorescence in situ hybridization (FISH) assays and RT-PCR tests. Although all of the EHEs were CAMTA1-positive in immunohistochemical staining, only five out of 18 EHEs (27.78%) positively expressed nuclear TFE3. The five TFE3-positive EHEs exhibited TFE3 gene break-apart in FISH assays. YAP1-TFE3 gene fusions were confirmed by RT-PCR. Interestingly, we observed CAMTA1 gene break-apart in all of the five TFE3-positive EHEs via FISH assays, and four out of the five TFE3-positive EHEs exhibited WWTR1-CAMTA1 gene fusions via RT-PCR. These results indicate that these two chromosomal alterations are not mutually exclusive but compossible in EHEs. Finally, primary tumor sites in TFE3-positive EHEs consistently contained single masses (P = 0.0359) with larger sizes (P = 0.0550) compared to TFE3-negative EHEs. Similar to previous reports, we observed well-formed vessels more frequently in TFE3-positive EHEs than in TFE3-negative EHEs (P = 0.0441). In addition, TFE3- positive EHEs tended to more frequently demonstrate high-grade nuclear atypia (P = 0.0654) and hypercellularity (P=0.0987) than TFE3-negative EHEs. Thus, we have now established two clinically distinct subgroups of EHEs: TFE3-positive and TFE3- negative EHEs.