title: Expression pattern of FGFR2, Grb2 and Plcγ1 acts as a novel prognostic marker of recurrence recurrence-free survival in lung adenocarcinoma.
abstract: Lung adenocarcinoma is characterized by complex biology involving alterations at the genomic and protein expression levels. FGFR2 mutation and/or amplification are key drivers of disease progression and drug resistance in lung adenocarcinoma patients. These genetic alterations drive oncogenic downstream signalling due to the deregulated activity of the receptor. We have previously reported that wild type FGFR2 provides a binding site for which two proteins, Grb2 and Plcγ1, compete in a concentration-dependent manner. Metastasis and invasion ensue when Plcγ1 prevails on the receptor giving rise to oncogenic outcome in the absence of gene mutation/deletion. The effect of this signalling mechanism on FGFR2-driven lung adenocarcinoma has not previously been considered. In this study we show that fluctuation in the combinatorial expression levels of FGFR2, Grb2 and Plcγ1 modulates cell invasive properties, tumor formation and is linked to recurrence-free survival in 150 lung adenocarcinoma patients. High levels of expression of FGFR2 and Plcγ1 in a low background of Grb2 significantly correlates with poor prognosis. On the other hand, low levels of expression of FGFR2 and Plcγ1 in a high background of Grb2 correlates with favourable prognosis. This study defines the expression pattern of FGFR2, Plcγ1 and Grb2 as a novel prognostic marker in human lung adenocarcinoma. Thus, consideration of the Grb2 and Plcγ1-mediated mechanism of FGFR2 regulation will enhance the therapeutic targeting of aberrant FGFR2 activity to provide the much-needed improvement to the treatment regimen of this high mortality disease.
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds Leeds, LS2 9JT, UK ; Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center Unit 1000, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Timsah
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds Leeds, LS2 9JT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berrout
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center Houston, Texas 77030, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Suraokar
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center Houston, Texas 77030, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center Houston, Texas 77030, USA.
authors.forename: Juhee
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center Houston, Texas 77030, USA.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M. D. Anderson Cancer Center Unit 1362, 7777 Knight Road, Houston, TX 77054, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas, M. D. Anderson Cancer Center Unit 63, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital Leeds, LS9 7TF, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Shires
authors.affiliation: Department of Genomic Medicine, The University of Texas, M. D. Anderson Cancer Center Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas, M. D. Anderson Cancer Center Unit 63, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Vallien
authors.affiliation: Department of Imaging Physics, University of Texas, M. D. Anderson Cancer Center Unit 1472, 1400 Pressler Street, Houston, TX 77030, USA.
authors.forename: Charles V
authors.initials: CV
authors.lastname: Kingsley
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center Houston, Texas 77030, USA.
authors.forename: IgnacioI
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds Leeds, LS2 9JT, UK ; Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center Unit 1000, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
keywords: SH3 domain; cancer of non-genetic origin; oncogenesis; proline-rich domain; receptor tyrosine kinase