Journal of Translational Medicine | |
Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma | |
Christopher L. Corless1  Jessica L. Davis1  Adam M. Burgoyne2  Rowan Ustoy3  Mayra Yebra3  Chih-Min Tang3  Sangkyu Noh3  Jason K. Sicklick3  Sudeep Banerjee3  Markku M. Miettinen4  | |
[1] Department of Pathology and Knight Cancer Institute, Oregon Health & Science University;Division of Hematology Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego;Division of Surgical Oncology, Department of Surgery, Moores Cancer Center, University of California, San Diego, UC San Diego Health Sciences;Laboratory of Pathology, National Cancer Institute; | |
关键词: Submucosal tumor; Gastric mass; Patched 1; GLI1; Hedgehog pathway; SMO inhibitor; | |
DOI : 10.1186/s12967-019-1995-z | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown