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

Journal of Translational Medicine

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