FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis
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Julia Elisabeth Fromme1,*, Katja Schmitz1,*, Astrid Wachter2, Marius Grzelinski3, Dirk Zielinski3, Christina Koppel3, Lena-Christin Conradi4, Kia Homayounfar4, Tabea Hugo1, Sara Hugo1, Laura Lukat1, Josef Rüschoff3, Philipp Ströbel1, Michael Ghadimi4, Tim Beißbarth2, Kirsten Reuter-Jessen1,**, Annalen Bleckmann2,5,** and Hans-Ulrich Schildhaus1,3,**
1Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
2Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
3Targos Molecular Pathology Inc., Kassel, Germany
4Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University, Goettingen, Germany
5Department for Hematology and Medical Oncology, University Hospital Göttingen, Göttingen, Germany
*These authors have contributed equally to this work
**KRJ, AB, HUS share senior authorship
Hans-Ulrich Schildhaus, email: Hans-Ulrich.Schildhaus@med.uni-goettingen.de
Keywords: colorectal cancer; metastases; FGFR3; fibroblast growth factor receptors; RNA in situ hybridization
Received: March 26, 2018 Accepted: July 12, 2018 Published: August 14, 2018
Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established.
Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors (FGFR1-4) and their ligands (FGF3, 4 and 19) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ. Results were correlated with clinico-pathologic data and molecular subtypes.
Results: Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111).
Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.
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