Stains
WWTR1
Copyright: 2003-2019, PathologyOutlines.com, Inc.
PubMed Search: WWTR1
WWTR1
Authors: Angela M.Y. Chan, M.Sc., Emeka Enwere, Ph.D.
Topic Completed: 1 April 2017
Minor changes: 8 December 2019
Copyright: 2003-2019, PathologyOutlines.com, Inc.
PubMed Search: WWTR1
Table of Contents
Definition / general | Essential features | Terminology | Sites | Pathophysiology | Clinical features | Case reports | Treatment | Microscopic (histologic) images | Positive stains | Negative stains | Board review style question #1 | Board review answer #1Cite this page: Chan A, Enwere E. WWTR1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainswwtr1.html. Accessed June 7th, 2020.
Definition / general
- WWTR1, also known as TAZ (Transcriptional coactivator with PDZ binding motif), is a transcriptional coactivator that regulates expression of genes involved in cell proliferation and differentiation
- The human WWTR1 gene codes for a protein with an apparent molecular weight of 50 - 55 kDa
Essential features
- WWTR1 is negatively regulated by the Hippo signal transduction pathway
- This pathway controls organ size by dynamically balancing the processes of cell proliferation and apoptosis (Nat Rev Cancer 2015;15:73)
- WWTR1 functions interchangeably with its paralog, Yes associated protein (YAP)
- In the absence of Hippo signaling, WWTR1 is predominantly present in the nucleus, where it interacts with various transcription factors to regulate gene expression
- In the presence of Hippo signaling, it is retained in the cytoplasm and degraded
- WWTR1 is overexpressed in many types of cancer (Cancer Cell 2016;29:783) and promotes metastasis through epithelial mesenchymal transition (Genes Dev 2012;26:54)
- The human WWTR1 gene is on chromosome 3q24
Terminology
- WWTR1 (WW Domain Containing Transcription Regulator 1)
- TAZ
Sites
- Ubiquitously expressed predominantly in the nucleus but cytoplasmic expression is likely in cells with active Hippo pathways
Pathophysiology
- Deletion of WWTR1 in mice leads to development of renal cysts and emphysema (Proc Natl Acad Sci U S A 2007;104:1631, Am J Physiol Renal Physiol 2008;294:F542) but the overall phenotype is remarkably mild
- This may be due to compensation for WWTR1 loss by the YAP paralog
Clinical features
- Over 90% of epithelioid hemangioendotheliomas contain a reciprocal t(1;3)(p36;q25) chromosomal translocation (Oncogene 2016;35:929)
- This results in the fusion of the N terminal of WWTR1 with the C terminal of CAMTA1, creating a putative oncogene (Sci Transl Med 2011;3:98ra82)
- Molecular confirmation of this translocation involves a break apart FISH assay; however, immunohistochemistry performed using an antibody raised against the C terminal of CAMTA1 may serve as a proxy, since CAMTA1 is not otherwise expressed in vascular endothelial tumors (Am J Surg Pathol 2016;40:94, Diagn Pathol 2016;11:75)
Case reports
- A rare case of epithelioid hemangioendothelioma as a primary thyroid tumor (Endocr Pathol 2016;27:147)
Treatment
- TAZ does not bind to DNA on its own but through interaction with TEAD transcription factors
- Interruption of the TAZ-TEAD interaction can potentially be useful in the inhibition of the oncogenic role of TAZ
- Currently no therapeutic is available to interrupt TAZ-TEAD interaction
- Verteporfin is shown to block YAP-induced tumorigenesis (Genes Dev 2012;26:1300)
Microscopic (histologic) images
Images hosted on other servers:
TAZ / YAP associated with increased grade
Staining of WWTR1 in osteosarcoma
activated across multiple
histological sarcoma types
Positive stains
- Various types of cancer: brain, colon, kidney, liver, lung, pancreas
Negative stains
- Skin, soft tissue
Board review style question #1
-
Which assay(s) would support a diagnosis of epithelioid hemangioendothelioma with WWTR1-CAMTA1 fusion?
- CAMTA1 immunohistochemistry
- WWTR1-CAMTA1 break apart FISH
- WWTR1 immunohistochemistry
- (a) or (b)
- (b) or (c)
Board review answer #1
D. While break apart FISH is sufficient for molecular confirmation, CAMTA1 mis-expression in epithelioid hemangioendotheliomas may also be indicative of this translocation event.
