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

Abstract

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.

Anti-KIT DNA Aptamer for Targeted Labeling of Gastrointestinal Stromal Tumor

“…Fresh tumor tissue was dissociated into single-cell suspensions using the gentleMACS Dissociator (Miltenyi Biotec) as described previously (21). Solid tissues were cut into 5-mm size pieces and were transferred to a gentleMACS C-Tube containing RPMI media and MACS human tumor dissociation enzyme cocktail (Miltenyi Biotec) according to the manufacturer's instructions for tough tumor tissue (h_Tumor_01).…”

Recent developments in gastroesophageal mesenchymal tumours

“…36 Plexiform fibromyxoma harbours alterations in the hedgehog signalling pathway, including MALAT1-GLI1 gene fusions (approximately 20-40% of cases), 36,37 GLI1 amplification (approximately 10-15%) 37 and PTCH1 deletions (approximately 20%). 38 The MALAT1-GLI1 gene fusion juxtaposes the promoter of MALAT1, a gene for a non-coding RNA normally expressed at high levels in multiple tissue types, 39 with GLI1, a transcription factor expressed in hedgehog signalling that has been investigated as a potential therapeutic target. 40 The hedgehog pathway is important for regulating stem cell differentiation, organogenesis and tissue regeneration; constitutive activation of hedgehog signalling is implicated in a wide variety of tumour types, including those of Gorlin syndrome.…”

Intracardiac tumor as a rare manifestation of genetic syndromes—presentation of a family with Gorlin syndrome and a literature review

“…Instead, loss of PTCH1 locus has been shown in cardiac fibroma tissue (Scanlan et al 2008 ). Recently, in a mixed fibrous/myxoid type of gastric neoplasm called plexiform fibromyxoma, a link was established between Hedgehog signaling (Hh) and loss of PTCH1 (Banerjee et al 2019 ). Treatment of the primary tumor cells with the Hh pathway inhibitor, sonidegib (LDE225, Novartis), resulted in dose-dependent cell killing (Banerjee et al 2019 ).…”

“…Recently, in a mixed fibrous/myxoid type of gastric neoplasm called plexiform fibromyxoma, a link was established between Hedgehog signaling (Hh) and loss of PTCH1 (Banerjee et al 2019 ). Treatment of the primary tumor cells with the Hh pathway inhibitor, sonidegib (LDE225, Novartis), resulted in dose-dependent cell killing (Banerjee et al 2019 ). This provides rationale for the future therapeutic trials of other tumors in the setting of PTCH1 loss, and it would be interesting to see how various types of tumors in Gorlin syndrome respond to the similar treatment.…”