TY - JOUR
T1 - Molecular modeling and functional analysis of exome sequencing-derived variants of unknown significance identify a novel, constitutively active FGFR2 mutant in cholangiocarcinoma
AU - Egan, Jan B.
AU - Marks, David L.
AU - Hogenson, Tara L.
AU - Vrabel, Anne M.
AU - Sigafoos, Ashley N.
AU - Tolosa, Ezequiel J.
AU - Carr, Ryan M.
AU - Safgren, Stephanie L.
AU - Hesles, Elisa Enriquez
AU - Almada, Luciana L.
AU - Romecin-Duran, Paola A.
AU - Iguchi, Eriko
AU - Ala'Aldeen, Aryan
AU - Kocher, Jean Pierre A.
AU - Oliver, Gavin R.
AU - Prodduturi, Naresh
AU - Mead, David W.
AU - Hossain, Asif
AU - Huneke, Norine E.
AU - Tagtow, Colleen M.
AU - Ailawadhi, Sikander
AU - Ansell, Stephen M.
AU - Banck, Michaela S.
AU - Bryce, Alan H.
AU - Carballido, Estrella M.
AU - Chanan-Khan, Asher A.
AU - Curtis, Kelly K.
AU - Resnik, Ernesto
AU - Gawryletz, Chelsea D.
AU - Go, Ronald S.
AU - Halfdanarson, Thorvardur R.
AU - Ho, Thai H.
AU - Joseph, Richard W.
AU - Kapoor, Prashant
AU - Mansfield, Aaron S.
AU - Meurice, Nathalie
AU - Rao, Amulya A.Nageswara
AU - Nowakowski, Grzegorz S.
AU - Pardanani, Animesh
AU - Parikh, Sameer A.
AU - Cheville, John C.
AU - Feldman, Andrew L.
AU - Ramanathan, Ramesh K.
AU - Robinson, Steven I.
AU - Tibes, Raoul
AU - Finnes, Heidi D.
AU - McCormick, Jennifer B.
AU - McWilliams, Robert R.
AU - Jatoi, Aminah
AU - Patnaik, Mrinal M.
AU - Silva, Alvin C.
AU - Wieben, Eric D.
AU - McAllister, Tammy M.
AU - Rumilla, Kandelaria M.
AU - Kerr, Sarah E.
AU - Lazaridis, Konstantinos N.
AU - Farrugia, Gianrico
AU - Keith Stewart, A.
AU - Clark, Karl J.
AU - Kennedy, Eileen J.
AU - Klee, Eric W.
AU - Borad, Mitesh J.
AU - Fernandez-Zapico, Martin E.
N1 - Publisher Copyright:
© 2018 American Society of Clinical Oncology.
PY - 2017
Y1 - 2017
N2 - Purpose 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. Materials and Methods 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. Results 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 to522VUSsof interest, including a largenumberof kinases.Tenreceptor tyrosine 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. Conclusion 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.
AB - Purpose 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. Materials and Methods 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. Results 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 to522VUSsof interest, including a largenumberof kinases.Tenreceptor tyrosine 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. Conclusion 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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UR - http://www.scopus.com/inward/citedby.url?scp=85077486674&partnerID=8YFLogxK
U2 - 10.1200/PO.17.00018
DO - 10.1200/PO.17.00018
M3 - Article
AN - SCOPUS:85077486674
SN - 2473-4284
VL - 2017
SP - 1
EP - 13
JO - JCO Precision Oncology
JF - JCO Precision Oncology
IS - 1
ER -