Identification of FGFR3-TACC3 gene fusion in metastatic gastric cancer
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Abstract
In preclinical cancer models, fibroblast growth factor receptor (FGFR) gene aberration has been known to be associated with increased tumor cell proliferation and survival in several cancer types. Oncogenic fusions consisting of FGFR3 and transforming acid coiled coil 3 (TACC3) had been identified as potential therapeutic target. We report on a gastric cancer patient with liver metastases who harbored FGFR3-TACC3 fusion which is extremely rare in gastrointestinal cancer. Herein, we report a case presentation with literature review of FGFR3-TACC3 fusion.
INTRODUCTION
Gastric cancer (GC) is the second most common cause of cancer-related deaths worldwide, and the prognosis of advanced gastric cancer is still poor [1,2]. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system consists of 18 ligands (FGFs) and four receptors (FGFR1-4) [3,4]. Upon ligand binding FGFRs activate several signaling cascades, particularly phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinases (MAPK)/extracellular-signal-regulated kinase (ERK) [5]. In turn, this leads to regulation of diverse cellular functions which play a pivotal role not only in physiological homeostasis but also in carcinogenesis, e.g. proliferation, motility, angiogenesis, anti-apoptosis and drug resistance [3,6]. More recently, FGFR fusion proteins have been increasingly detected in various human cancers, and transforming acid coiled coil 3 (TACC3) gene has been identified as an important partner of these FGFR fusions and was known to force dimerization and consequently activation of FGFR3 kinase activity in several solid tumors [7,8]. The contribution of such fusions to cancers of the upper digestive tract has remained largely unknown, but was detected in esophageal squamous cell carcinoma, recently [9,10]. Here we report a case of metastatic GC harboring an activating FGFR3-TACC3 mutation for the first time.
CASE REPORT
In August 2010, a 52-year-old man was referred to our hospital for treatment of gastric cancer which was identified during annual endoscopic examination as part of national cancer screening program in Korea. The initial computed tomography (CT) scan at diagnosis demonstrated wall thickening in the lesser curvature of the lower body without any evidence for distant metastasis. He received curative subtotal gastrectomy, Billroth I anastomosis, D2 dissection and the pathologic examination revealed a moderately-differentiated adenocarcinoma, pT3N0M0, stage IIA (erbb2 negative). As postoperative adjuvant treatment, the patient completed 8 cycles of TS-1 chemotherapy given the pathologic stage. During scheduled surveillance for recurrence, the patient developed multiple liver metastases after 15 months postsurgery (Fig. 1). Liver biopsy was performed and the pathology revealed metastasized gastric adenocarcinoma. He received first-line capecitabine/oxaliplatin (oxaliplatin 130 mg/m2 + capecitabine 1,000 mg/m2 by mouth twice a day, day 1 to 14) every 21 days, and achieved partial response for 5 months. Follow-up CT scan still showed 1.1 cm metastatic lesion in S6 which was further ablated by CT-guided percutaneous radiofrequency ablation (RFA). The patient received ramucirumab/paclitaxel with complete remission after RFA until he developed another liver metastases. We identified FGFR3-TACC3 fusion in his tumor using next-generation sequencing (NGS) platform that we routinely use in the clinic (OncomineTM Comprehensive Assay v3, www.thermofisher.com).
Computed tomography of the abdomen after 15 months since surgery. It showed multiple hepatic metastases, medium-sized and small nodules in the (A) right (arrow) and (B) left (arrow) hepatic lobes.
DISCUSSION
Recent advances in sequencing technologies have led to an increase in the discovery of novel and therapeutically actionable genomic alterations in a broad range of cancers. Comprehensive clinical sequencing programs for cancer patients have been initiated at a variety of medical centers including our center [11]. Recently, FGFR3-TACC3 gene fusion has been identified in several cancers including glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. We summarized the incidence of FGFR3-TACC3 rearrangements in various tumor types in Table 1 that had been reported in the literature [7,12-24]. To the best of our knowledge, FGFR3-TACC3 fusions have not previously been described in GC.
Cross-sectional studies and case series reporting positive FGFR-TACC3 fusions
FGFR3–TACC3 fusion proteins appear to localize to spindle poles and cause disruption of chromosome segregation and aneuploidy by a mechanism dependent on FGFR tyrosine kinase activity [25]. The tumor-initiating activity of the FGFR3- TACC3 fusion protein suggests that it has growth-promoting signaling functions that complement the loss of mitotic fidelity and aneuploidy to induce full-blown tumorigenesis. The clinical relevance of FGFR3-TACC3 has been underscored by preliminary results from clinical studies and case reports of tumor responses to the treatment with FGFR inhibitors. For instance, the phase I trial with FGFR inhibitor JNJ-42756493 including 65 patients with advanced solid tumors included 4 patients with FGFR3-TACC3 translocation [26]. We outlined the evidence from early phase clinical trials support that FGFR aberrations can represent targetable events and several clinical trials of FGFR inhibitors, including with BGJ398 (NCT01928459, NCT 01975701, NCT01697605, and NCT01004224), are currently under clinical development in Table 2 [13].
Summary of FGFR inhibitors currently investigated in clinical trials
This report is the first to identify FGFR3-TACC3 fusion proteins in gastric cancer, and it provides proof of concept that treating with an FGFR inhibitor can result in clinical benefit in metastatic GC carrying FGFR3-TACC3 translocation in agreement with results observed in other malignancies. In addition, our findings suggest the importance of a comprehensive genomic profiling approach able to detect all classes of genomic alterations including uncommon gene fusions to reveal potentially targetable somatic alterations.
Notes
No potential conflict of interest relevant to this article was reported.