%0 Journal Article %1 Haller2015 %A Haller, Florian %A Bieg, Matthias %A Moskalev, Evgeny A. %A Barthelmeß, Sarah %A Geddert, Helene %A Boltze, Carsten %A Diessl, Nicolle %A Braumandl, Karin %A Brors, Benedikt %A Iro, Heinrich %A Hartmann, Arndt %A Wiemann, Stefan %A Agaimy, Abbas %D 2015 %J Am J Pathol %K ABI-DKFZ %N 2 %P 563--571 %R 10.1016/j.ajpath.2014.10.019 %T Recurrent mutations within the amino-terminal region of $\beta$-catenin are probable key molecular driver events in sinonasal hemangiopericytoma. %U http://dx.doi.org/10.1016/j.ajpath.2014.10.019 %V 185 %X Sinonasal hemangiopericytoma (SN-HPC) is an uncommon, site-specific, low-grade mesenchymal neoplasm of probable perivascular myoid cell origin. In contrast to solitary fibrous tumors of soft tissue and sinonasal tract origin, SN-HPCs were recently shown to lack recurrent NAB2-STAT6 fusion variants. Other molecular alterations known to occur in some of soft tissue perivascular myoid cell neoplasms were also absent in SN-HPC; thus, the molecular pathogenesis of SN-HPCs remained unknown. Guided by whole-genome sequencing combined with RNA sequencing of an index case, we analyzed a total of six SN-HPCs for mutations within the amino-terminal region of the gene CTNNB1 (cadherin-associated protein), β 1, 88 kDa, encoding β-catenin. All six cases showed missense mutations, with amino acid substitutions clustering at positions 33 to 45, corresponding to the recognition site of the β-catenin destruction complex. Similar CTNNB1 mutations have been described in a variety of epithelial and mesenchymal neoplasms. These mutations prevent β-catenin phosphorylation and proteasomal degradation but promote its nuclear accumulation and subsequent increased transcription of Wingless-related integration site target genes. Consistent with these molecular findings, β-catenin IHC showed consistent diffuse and strong nuclear staining of the tumor cells in all six SN-HPCs. Our results highlight, for the first time, CTNNB1 mutations as the likely initiating molecular events driving SN-HPC tumorigenesis, which places SN-HPC among the growing family of β-catenin-driven mesenchymal neoplasms.

@article{Haller2015, __markedentry = {[bbrors:6]}, abstract = {Sinonasal hemangiopericytoma (SN-HPC) is an uncommon, site-specific, low-grade mesenchymal neoplasm of probable perivascular myoid cell origin. In contrast to solitary fibrous tumors of soft tissue and sinonasal tract origin, SN-HPCs were recently shown to lack recurrent NAB2-STAT6 fusion variants. Other molecular alterations known to occur in some of soft tissue perivascular myoid cell neoplasms were also absent in SN-HPC; thus, the molecular pathogenesis of SN-HPCs remained unknown. Guided by whole-genome sequencing combined with RNA sequencing of an index case, we analyzed a total of six SN-HPCs for mutations within the amino-terminal region of the gene CTNNB1 (cadherin-associated protein), β 1, 88 kDa, encoding β-catenin. All six cases showed missense mutations, with amino acid substitutions clustering at positions 33 to 45, corresponding to the recognition site of the β-catenin destruction complex. Similar CTNNB1 mutations have been described in a variety of epithelial and mesenchymal neoplasms. These mutations prevent β-catenin phosphorylation and proteasomal degradation but promote its nuclear accumulation and subsequent increased transcription of Wingless-related integration site target genes. Consistent with these molecular findings, β-catenin IHC showed consistent diffuse and strong nuclear staining of the tumor cells in all six SN-HPCs. Our results highlight, for the first time, CTNNB1 mutations as the likely initiating molecular events driving SN-HPC tumorigenesis, which places SN-HPC among the growing family of β-catenin-driven mesenchymal neoplasms.}, added-at = {2015-06-29T14:32:37.000+0200}, author = {Haller, Florian and Bieg, Matthias and Moskalev, Evgeny A. and Barthelme{\ss}, Sarah and Geddert, Helene and Boltze, Carsten and Diessl, Nicolle and Braumandl, Karin and Brors, Benedikt and Iro, Heinrich and Hartmann, Arndt and Wiemann, Stefan and Agaimy, Abbas}, biburl = {https://www.bibsonomy.org/bibtex/2b42cbb9c2f8fa020c5a8ce4a305137d2/juraeva}, doi = {10.1016/j.ajpath.2014.10.019}, institution = {Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.}, interhash = {9fb8cfed8fd8aa3a5f51abc6d8b2a379}, intrahash = {b42cbb9c2f8fa020c5a8ce4a305137d2}, journal = {Am J Pathol}, keywords = {ABI-DKFZ}, language = {eng}, medline-pst = {ppublish}, month = feb, number = 2, owner = {bbrors}, pages = {563--571}, pii = {S0002-9440(14)00613-0}, pmid = {25482924}, timestamp = {2015-06-29T14:34:20.000+0200}, title = {Recurrent mutations within the amino-terminal region of $\beta$-catenin are probable key molecular driver events in sinonasal hemangiopericytoma.}, url = {http://dx.doi.org/10.1016/j.ajpath.2014.10.019}, volume = 185, year = 2015 }