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Ref Type Journal Article
PMID (30761385)
Authors Egan JB, Marks DL, Hogenson TL, Vrabel AM, Sigafoos AN, Tolosa EJ, Carr RM, Safgren SL, Hesles EE, Almada LL, Romecin-Duran PA, Iguchi E, Ala'Aldeen A, Kocher JA, Oliver GR, Prodduturi N, Mead DW, Hossain A, Huneke NE, Tagtow CM, Ailawadhi S, Ansell SM, Banck MS, Bryce AH, Carballido EM, Chanan-Khan AA, Curtis KK, Resnik E, Gawryletz CD, Go RS, Halfdanarson TR, Ho TH, Joseph RW, Kapoor P, Mansfield AS, Meurice N, Nageswara Rao AA, Nowakowski GS, Pardanani A, Parikh SA, Cheville JC, Feldman AL, Ramanathan RK, Robinson SI, Tibes R, Finnes HD, McCormick JB, McWilliams RR, Jatoi A, Patnaik MM, Silva AC, Wieben ED, McAllister TM, Rumilla KM, Kerr SE, Lazaridis KN, Farrugia G, Stewart AK, Clark KJ, Kennedy EJ, Klee EW, Borad MJ, Fernandez-Zapico ME
Title Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma.
Journal JCO precision oncology
Vol 2017
Issue
Date 2017
URL
Abstract Text Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs.Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity.The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases. Ten receptortyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit.The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians' ability to make informed treatment decisions.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 F276C missense gain of function FGFR2 F276C lies within the Ig-like C2-type domain 3 of the Fgfr2 protein (UniPort.org). F276C results in increased Fgfr2 expression, altered cellular localization, and ligand-independent Erk phosphorylation in culture (PMID: 30761385).
FGFR2 K41E missense no effect - predicted FGFR2 K41E lies within the Ig-like C2-type domain 1 of the Fgfr2 protein (UniProt.org). K41E results in decreased Fgfr2 expression, but demonstrates subcellular localization, basal and ligand-dependent phosphorylation of Erk levels similar to wild-type protein in culture (PMID: 30761385), and therefore, is predicted to have no effect on Fgfr2 protein function.
KDR G539R missense gain of function - predicted KDR (VEGFR2) G539R lies within the Ig-like C2-type domain 5 of the Kdr (Vegfr2) protein (UniProt.org). G539R is associated with increased expression of Kdr (Vegfr2) and increased ligand-dependent Erk phosphorylation in cell culture (PMID: 30761385), and therefore, is predicted to lead to a gain of Kdr (Vegfr2) protein function.
KDR G55E missense loss of function KDR (VEGFR2) G55E lies within the Ig-like C2-type domain 1 of the Kdr (Vegfr2) protein (UniProt.org). G55E results in decreased expression of Kdr (Vegfr2), reduced basal level and ligand-dependent Erk phosphorylation in cell culture (PMID: 30761385).
PDGFRB V258L missense no effect - predicted PDGFRB V258L lies within the Ig-like C2-type domain 3 of the Pdgfrb protein (UniProt.org). V258L results in Pdgfrb expression, phosphorylation of Erk and subcellular localization similar to wild-type Pdgfrb (PMID: 30761385), and therefore, is predicted to have no effect on Pdgfrb protein function.
PDGFRB V316M missense no effect - predicted PDGFRB V316M lies within the extracellular domain of the Pdgfrb protein (Uniprot.org). V316M results in decreased Pdgfrb expression, but leads to Erk phosphorylation and subcellular localization similar to wild-type Pdgfrb (PMID: 30761385), and therefore, is predicted to have no effect on Pdgfrb protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 F276C intrahepatic cholangiocarcinoma predicted - sensitive Infigratinib Case Reports/Case Series Actionable In a Phase II trial, Truseltiq (infigratinib) treatment resulted in partial response after 2 months of therapy and response was maintained for 4 months in a patient with advanced intrahepatic cholangiocarcinoma harboring a FGFR2 F276C mutation, which is consistent with inhibition of Erk signaling in cholangiocarcinoma cells expressing FGFR2 F274C in culture (PMID: 30761385; NCT02150967). 30761385