Faculty Collaboration Database

The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy. Cancer Res 2012 Nov 15;72(22):5683-91

Date

09/19/2012

Pubmed ID

22986737

DOI

10.1158/0008-5472.CAN-12-2102

Scopus ID

2-s2.0-84869209181 (requires institutional sign-in at Scopus site)   44 Citations

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.

Author List

Serra S, Zheng L, Hassan M, Phan AT, Woodhouse LJ, Yao JC, Ezzat S, Asa SL

Author

Alexandria T. Phan MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents
Carcinoma, Neuroendocrine
Cell Growth Processes
Cell Line, Tumor
Disease Progression
Everolimus
Female
Humans
Male
Mice
Mice, SCID
Middle Aged
Pancreatic Neoplasms
Polymorphism, Single Nucleotide
Receptor, Fibroblast Growth Factor, Type 4
Sirolimus
TOR Serine-Threonine Kinases
Xenograft Model Antitumor Assays
Young Adult