1.15 An Inactivating Patched 1 Gene Mutation in the Hedgehog Pathway Defines a New Subset of Plexiform Fibromyxoma

S. Banerjee1, C. Tang1, M. Yerba1, R. Ustoy1, A. M. Burgoyne2, T. J. Savides3, A. M. Tipps4, J. K. Sicklick1  1University Of California – San Diego,Department Of Surgery,San Diego, CA, USA 2University Of California – San Diego,Department Of Medical Oncology,San Diego, CA, USA 3University Of California – San Diego,Department Of Gastroenterology,San Diego, CA, USA 4University Of California – San Diego,Department Of Pathology,San Diego, CA, USA


Plexiform fibromyxoma (PF) is a rare submucosal gastric tumor that can be confused with gastrointestinal stromal tumor (GIST). While slow growth and lack of metastases suggest an indolent natural history, these so-called benign tumors often present with upper GI bleeding and have a propensity to locally recur. As there are no known drug treatments for PF, resection remains the only treatment. In 2016, the first insight into the molecular biology of 16 PFs demonstrated 4 tumors (25%) with activation of the GLI1 oncogene, a transcription factor in the Hedgehog (Hh) signaling pathway. Despite this discovery, the underlying biology of most PFs remains unknown.



Following patient consent to an IRB-approved protocol, clinical data and tumor tissue were collected. After pathologic diagnosis, FoundationOne Heme next generation sequencing (NGS) of >400 genes was performed. Real-time reverse transcription polymerase chain reaction (RT-PCR) for Hh pathway components was performed on mRNA extracted from resected tumor tissue. Additionally, tumor cells were dissociated, placed in primary culture, treated with Hh inhibitor, sonidegib (Novartis/Sun Pharma), and assessed for cell viability using Cell Titer Glo assay.



We report a 65-year-old male that presented with acute upper GI bleeding from a 5.0 cm gastric mass. Upper endoscopy revealed an ulcerated tumor and biopsy demonstrated a PF. He underwent partial gastrectomy with R0 resection. The immunohistochemical profile (positive: SMA; negative: CD34, S-100, DOG-1, CD117) and histomorphology (transmural myxoid stroma, plexiform growth pattern with spindle cells, and prominent thin capillaries) were consistent with the diagnosis of PF. On NGS, an inactivating Patched 1 (PTCH1) deletion of exons 15-24 was detected. PTCH1, a known tumor suppressor gene implicated in basal cell carcinoma and medulloblastoma tumorigenesis, functions upstream of GLI1 in the Hh pathway. Thus, this tumor’s loss of PTCH1 function can induce downstream GLI1 activation and transcription of target genes. To confirm activation of the Hh pathway in PF, quantitative RT-PCR analysis of mRNA transcripts demonstrated expression of SMO and GLI1, as well as downstream GLI1 transcriptional targets, including Cyclin D1 and HHIP. In turn, treatment with Hh pathway inhibitor, sonidegib (50 μM), demonstrated cell killing with 97.4% efficiency (P=0.0002) after 48-hours.



For the first time, we report that an inactivating PTCH1 mutation is associated with the development of plexiform fibromyxoma. We show that tumor suppressor gene alterations, rather than oncogenic mutations, within the Hh pathway can also cause plexiform fibromyxoma. In turn, targeted Hh pathway inhibition may represent a viable approach for treating a subset of recurrent plexiform fibromyxomas. Further studies are warranted to investigate the clinical efficacy of these agents in appropriately selected patients.