Abstract
BackgroundPlexiform 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.MethodsNext 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.ResultsEight 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.ConclusionsFor 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.
Highlights
Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor
Acquisition of clinical data, and conducting experimental procedures on biological samples was approved or exempt by each institutional IRB [UC San Diego Human Research Protections Program Institutional Review Board (IRB) Protocol #090401, NCI Office of Human Subjects Research (OHSR) IRB exemption was granted for work with anonymized annotated human samples, and Oregon Health & Science University (OHSU) IRB exemption was granted for contribution of one patient to the study cohort]
We show that targeted SMO inhibition in vitro, which lies downstream of Patched 1 (PTCH1), but upstream of GLI1, leads to dose-dependent cell killing of PF cells
Summary
Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. 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. Both types of GLI1 genomic alterations resulted in overexpression of GLI1 protein and activation of Hh signaling This highly conserved pathway has been implicated in the biology of several types of cancers, including gastroblastoma [6], basal cell carcinoma [7], medulloblastoma [8], rhabdomyosarcoma [9], hepatocellular carcinoma [10], and GIST [11], as well as tumors with plexiform and fibromyxoid histologies [12]. Only SMO and PTCH1-altered tumors can be targeted with the three FDA-approved SMO inhibitors, namely sonidegib (Novartis/Sun), vismodegib (Genetech-Roche), and glasdegib (Pfizer)
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