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Background  Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called “benign” tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the  GLI1  oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown.    Methods  Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment.    Results  Eight patients with PF were identified and 5 patients’ tumors were analyzed by NGS. An index case had a mono-allelic  PTCH1  deletion of exons 15–24 and a second case, identified in a validation cohort, also had a  PTCH1  gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components,  SMO  and  GLI1 , as well as GLI1 transcriptional targets,  CCND1  and  HHIP . In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing.    Conclusions  For the first time, we report a novel association between  PTCH1  inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas.    Electronic supplementary material  The online version of this article (10.1186/s12967-019-1995-z) contains supplementary material, which is available to authorized users.

Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma