title: The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy.
abstract: Pancreatic neuroendocrine tumors (pNET), also known as islet cell tumors, exhibit a wide range of biologic behaviors ranging from long dormancy to rapid progression. Currently, there are few molecular biomarkers that can be used to predict recurrence/metastasis or response to therapy. This study examined the predictive and prognostic value of a single nucleotide polymorphism substituting an arginine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain. We established the FGFR4 genotype of 71 patients with pNETs and correlated genotype with biologic behavior. We created an in vivo model of pNET with BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to examine response to the mTOR inhibitor everolimus. We then validated the predictive results of experimental studies in a group of patients treated with everolimus. FGFR4-R388 is associated with more aggressive clinical behavior in patients with pNETs with a statistically significant higher risk of advanced tumor stage and liver metastasis. Using an orthotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intraperitoneal spread and metastatic growth within the liver. Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsiveness to everolimus. Concordantly, there was a statistically significant reduction in response to everolimus in patients with FGFR4-R388. Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predictive marker of potential therapeutic importance in this disease.
authors.affiliation: Departments of Pathology, Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Serra
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Manal
authors.initials: M
authors.lastname: Hassan
authors.forename: Alexandria T
authors.initials: AT
authors.lastname: Phan
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Woodhouse
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus