title: Recurrent mutations within the amino-terminal region of β-catenin are probable key molecular driver events in sinonasal hemangiopericytoma.
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.
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany. Electronic address: florian.haller@uk-erlangen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bieg
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Moskalev
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Barthelmeß
authors.affiliation: Institute of Pathology, St Vincent's Hospital, Karlsruhe, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Geddert
authors.affiliation: Institute of Pathology, SRH-Klinikum, Gera, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Boltze
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Diessl
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Braumandl
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Consortium for Translational Cancer Research, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Iro
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany; Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D005260:Female; D006393:Hemangiopericytoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D009669:Nose Neoplasms / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; D051176:beta Catenin