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FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study.

ABSTRACT: In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials.FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed.The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (P<0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P=0.0073) and UK (OS: 0.45 vs 1.9 years, P<0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P=0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour.A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive.

SUBMITTER: Su X

PROVIDER: S-EPMC3929881 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study.

Su X X Zhan P P Gavine P R PR Morgan S S Womack C C Ni X X Shen D D Bang Y-J YJ Im S-A SA Ho Kim W W Jung E-J EJ Grabsch H I HI Kilgour E E

British journal of cancer 20140123 4

<h4>Background</h4>In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials.<h4>Methods</h4>FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed.<h4>Results</h4>The prevalence of FGFR2 amplification was similar between the three cohorts ( ...[more]

PMID: 24457912

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Project description:Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

Dataset Information

FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study.

Publications

FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study.

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