FGFR2 fusions as novel oncogenic drivers in gastrointestinal stromal tumors: Two case reports and review of literature

Abstract

BACKGROUND

Gastrointestinal stromal tumors (GISTs) are generally characterized by driver mutations in KIT or PDGFRA. However, the molecular landscape of wild-type GISTs remains complex, posing significant therapeutic challenges. Recent evidence has indicated alterations in FGFR2 as potential oncogenic drivers in patients with various cancers. However, the role of these drivers in GIST pathogenesis remains underexplored.

CASE SUMMARY

We retrospectively evaluated two patients with GIST, diagnosed between August 2021 and July 2022, harboring FGFR2 mutations through hybrid capture-based next-generation sequencing (NGS). We analyzed their clinicopathological characteristics, treatment response, and long-term follow-up data. Both patients, a 47-year-old man (case 1) and a 43-year-old woman (case 2), underwent successful surgical resection and received adjuvant imatinib therapy. They achieved sustained remission with a median follow-up of 28 months. Notably, the NGS revealed novel FGFR2 rearrangements, an FGFR2-CIT/intergenic-FGFR2 fusion in case 1 and FGFR2-CAMK2G/FGFR2-VCL fusions in case 2 without canonical KIT or PDGFRA mutations. Both patients exhibited a favorable response to standard imatinib treatment.

CONCLUSION

Our findings provided preliminary evidence that novel FGFR2 fusions might act as primary oncogenic drivers in a rare subset of KIT/PDGFRA wild-type GISTs. These cases highlight the importance for comprehensive genomic profiling and suggest that fibroblast growth factor receptor-targeted inhibitors could be a potential therapeutic strategy for advanced or imatinib-resistant diseases, warranting further investigation in larger cohorts.

Key Words: Gastrointestinal stromal tumor; FGFR2 rearrangement; Next-generation sequencing; Imatinib; Case report

Core Tip: Herein, we report, for the first time, novel FGFR2 rearrangements FGFR2-CIT/intergenic-FGFR2 and FGFR2-CAMK2G/FGFR2-VCL fusions as potential primary oncogenic drivers in two patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors (GISTs). Both patients achieved sustained remission following adjuvant imatinib, challenging the notion that non-canonical alterations preclude tyrosine kinase inhibitor response. These findings might expand the molecular spectrum of GISTs and suggest that FGFR2 fusions might define a distinct subtype with potential sensitivity to FGFR-targeted therapies, offering new avenues for precision treatment in imatinib-resistant or advanced disease cases.

INTRODUCTION

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, originating from interstitial cells of Cajal or their precursors[1]. These tumors can arise anywhere along the gastrointestinal tract, with the stomach and small intestine being the most frequent sites[2]. The molecular pathogenesis of GISTs is well-characterized: Over 80% of cases are driven by mutually exclusive gain-of-function mutations in the receptor tyrosine kinase genes KIT and PDGFRA[3]. The discovery of these driver mutations revolutionized management of GIST, as targeted therapy with tyrosine kinase inhibitors (TKIs) such as imatinib mesylate has become the standard of care for advanced or surgically unresectable disease[4,5].

Despite the remarkable success of TKI therapy in KIT/PDGFRA-mutant GISTs, a significant subset of tumors, known as wild-type GISTs, lacks these canonical mutations. These cases account for approximately 10%-15% of all GISTs and are often characterized by a heterogeneous molecular landscape, including mutations in SDHA/SDHB/SDHC/SDHD subunits, NF1, or genes within the RAS-mitogen-activated protein kinase (MAPK) signaling pathway[6,7]. The diverse molecular drivers and often limited response to standard imatinib treatment present substantial therapeutic challenges in patients with wild-type GISTs, highlighting a critical need for a deeper understanding about their underlying oncogenic mechanisms and identifying novel actionable targets[8,9].

The FGFR family of tyrosine kinases plays a crucial role in cell proliferation, survival, and differentiation. Aberrant activation of FGFR signaling, primarily through gene fusions, amplifications, or point mutations, is a well-established oncogenic event in patients with various solid tumors[10]. For instance, FGFR2 fusions are a key molecular subgroup in intrahepatic cholangiocarcinoma, where they serve as predictive biomarkers for response to FGFR-specific inhibitors such as pemigatinib and futibatinib[11,12]. Similarly, FGFR2 alterations have been implicated in the pathogenesis of gastric cancer and other malignancies, driving tumor growth and metastasis by activating downstream signaling pathways such as the RAS-MAPK and phosphatidylinositol 3-kinase/protein kinase B pathways[13,14]. Although the role of FGFR signaling in patients with other cancer types is well-documented, its contribution to the pathogenesis of GISTs remains uninvestigated, particularly in the context of primary driver events in patients with wild-type tumors[15].

In this two-case series, we aimed to bridge the above-mentioned knowledge gap by describing the clinicopathological features and treatment outcomes in two patients with GISTs driven by novel FGFR2 rearrangements. Both patients were diagnosed using comprehensive genomic profiling via next-generation sequencing (NGS), identifying unique FGFR2 fusions without canonical KIT or PDGFRA mutations. Our findings could provide novel insights into the molecular landscape of GISTs and underscore the critical importance of NGS for identifying rare, actionable mutations. We also discuss the potential therapeutic implications of FGFR2 alterations in patients with GISTs, laying the foundation for future investigations into FGFR-targeted therapies for this challenging molecular subset.

CASE PRESENTATION

Chief complaints

Case 1: A 47-year-old man presented with a 2-week history of dull, intermittent epigastric pain and a progressively enlarging palpable upper abdominal mass.

Case 2: A 43-year-old woman was referred to our hospital due to a substantial space-occupying lesion in the small intestine detected by computed tomography (CT) during a physical examination.

History of present illness

Case 1: The patient reported no associated symptoms such as dysphagia, early satiety, weight loss, or gastrointestinal bleeding.

Case 2: The patient was asymptomatic prior to the incidental finding.

History of past illness

Case 1: The patient had no significant medical history.

Case 2: Not specified.

Personal and family history

Case 1: He had no known family history of cancer. Physical examination upon admission: A thorough physical examination revealed a firm, non-tender, and mobile mass in the left upper quadrant of the abdomen.

Case 2: Not specified.

Physical examination

Cases 1 and 2: Not specified.

Laboratory examinations

Cases 1 and 2: Not specified.

Imaging examinations

Case 1: A contrast-enhanced CT of the abdomen showed a large, well-circumscribed, exophytic mass originating from the greater curvature of the stomach, measuring approximately 5.0 cm × 6.0 cm (Figure 1A). Enhanced magnetic resonance imaging of the stomach revealed an irregular mass-like abnormal signal focus in the greater curvature of the gastric fundus, with a clear edge, approximately 53 mm × 34 mm in size. The mass showed high signal on T2-weighted imaging and diffusion weighted imaging, low signal on T1-weighted imaging, and significant enhancement post-contrast (Figure 1B). The imaging findings were suggestive of a mass in the gastric fundus on the greater curvature, considered a solid tumor (extrinsic growth type).

Figure 1 Imaging examinations. A: Computed tomography scan indicates a mass on the greater curvature side of the stomach; B: Magnetic resonance indicates a mass on the greater curvature side of the stomach.

Case 2: CT scan revealed a solid mass lesion in the small intestine within the abdominal cavity (Figure 2).

Figure 2 Computed tomography shows a solid mass lesion in the small intestine within the abdominal cavity.

FINAL DIAGNOSIS

Case 1

Pathological diagnosis confirmed a moderately risky GIST. Microscopic examination confirmed a spindle cell type GIST (Figure 3A). The tumor size was 5.8 cm × 5.5 cm × 4.0 cm, with a mitotic rate of < 5/5 mm². Immunohistochemical results were: Creatine kinase (full specimen) (-), S-100 (-), smooth muscle actin (SMA) (-), anaplastic lymphoma kinase (-), SOX10 (-); Desmin (+), cluster of differentiation (CD) 34 (+), trimethylated histone H3 at lysine 27 (+); CD117 (partially +); DOG1 (strongly +); β-catenin(cytoplasmic +); SDHB expression was retained; Ki-67 proliferation index was approximately 2%.

Figure 3 Microscopic examination. A: Confirmed that this was a spindle cell type gastrointestinal stromal tumors; B: Indicates a composition of spindle-shaped cells.

Hybrid capture-based NGS was performed on the tumor tissue. This analysis confirmed that the tumor was wild-type, as no pathogenic mutations in the canonical KIT or PDGFRA genes were detected. Notably, the NGS panel revealed two novel gene fusions involving FGFR2: An FGFR2-CIT fusion and an intergenic-FGFR2 rearrangement. No other known driver mutations (e.g., in SDH or NF1 genes) were identified.

Case 2

Postoperative histopathological examination of the resected specimen revealed multiple small intestinal masses (largest 9 cm, smallest 2 cm). Microscopically, the tumor was composed of spindle-shaped cells, with moderate atypia and a mitotic rate of approximately 4/5 mm² (Figure 3B). The pathological diagnosis was high-risk multiple GISTs of the small intestine. Immunohistochemical results were: CD117 (+), DOG1 (+), SMA (-), S100 (slightly +), Ki67 (+, 5%), desmin (-). Similar to case 1, NGS performed on the tumor tissue did not detect any KIT or PDGFRA mutations. Instead, it revealed two distinct FGFR2 rearrangements: An FGFR2-CAMK2G fusion and an FGFR2-VCL fusion.

TREATMENT

Case 1

The patient underwent laparoscopic gastric tumor resection (R0 resection).

Case 2

The patient underwent surgical resection of the small intestinal masses.

OUTCOME AND FOLLOW-UP

Case 1

Following surgery, the patient was started on adjuvant therapy with imatinib mesylate at 400 mg daily. He tolerated the treatment well. During a median follow-up period of 28 months, regular surveillance showed no evidence of local recurrence or distant metastasis. The patient remains in sustained remission and continues to take imatinib.

Case 2

Postoperatively, the patient was started on adjuvant imatinib mesylate at 400 mg daily. She showed good tolerance to the medication. During the last follow-up, 26 months after surgery, the patient was in continuous complete remission without signs of recurrence or metastasis. She continues to receive adjuvant imatinib therapy.

DISCUSSION

This report represents one of the first detailed clinical case series describing novel FGFR2 fusions as potential primary oncogenic drivers in patients with a rare subset of wild-type GISTs. The identification of FGFR2-CIT/intergenic-FGFR2 and FGFR2-CAMK2G/FGFR2-VCL fusions in these two cases significantly expands our understanding about the molecular landscape of GISTs and highlights a new potential therapeutic target for this challenging tumor type.

Most GISTs are driven by canonical gain-of-function mutations in KIT or PDGFRA[16,17]. However, approximately 10%-15% of GISTs are wild-type for these genes and are characterized by a heterogeneous molecular profile, including mutations in SDH subunits, NF1, or genes related to the RAS-MAPK signaling pathway[18,19]. Our discovery adds FGFR2 fusions to this growing list of drivers. The proposed mechanism of action, similar to that in other tumors, involves the 5’ partner genes (CIT, CAMK2G, VCL) providing dimerization domains that lead to ligand-independent, constitutive activation of the FGFR2 kinase domain, thereby promoting oncogenesis[20,21].

An intriguing and complex finding in our cases is the favorable response of both patients to adjuvant imatinib therapy, despite the absence of a classic KIT/PDGFRA mutations. Although imatinib is primarily a KIT/PDGFRA inhibitor, its clinical benefit here might be speculative. One hypothesis is a possible off-target inhibitory effect on the FGFR2 fusion protein or other critical downstream kinases[22-25]. Another possibility is that these tumors, despite their high-risk classification, possessed a relatively indolent biological behavior; the role of imatinib in their sustained remission is difficult to ascertain from this limited series[26-29]. This observation underscores the need for further mechanistic studies, such as in vitro drug sensitivity assays, to determine the precise reason for the imatinib response.

The identification of FGFR2 fusions opens a new avenue for targeted therapy, particularly in patients with advanced or imatinib-resistant disease[30-32]. In malignancies such as intrahepatic cholangiocarcinoma, FGFR2 fusions are established oncogenic drivers and predictive biomarkers for response to potent FGFR-specific inhibitors such as pemigatinib, futibatinib, and infigratinib[33-35]. Therefore, in patients with wild-type GIST who progress on standard TKIs, screening for FGFR2 alterations could be a promising strategy for guiding treatment with FGFR inhibitors.

This case series highlights the crucial role of comprehensive genomic profiling using NGS in modern GIST management. Conventional diagnostics are often insufficient to uncover rare molecular drivers in patients with wild-type GISTs[36]. Using NGS allowed us to identify these novel FGFR2 fusions, which would have otherwise been missed. This supports the consideration of NGS as a standard diagnostic component for all KIT/PDGFRA wild-type GISTs to enable precision-based therapeutic interventions[29,37].

Despite the compelling nature of our findings, this study has significant limitations. First, being a report of only two cases, our findings might lack generalizability; the prevalence of FGFR2 fusions in the wider wild-type GIST population remains unknown. Second, our study might lack functional validation[38]. Future research, including in vitro and in vivo experiments, is essential for confirming the oncogenicity of these specific FGFR2 fusions and to assess their sensitivity to various TKIs[39]. Third, the absence of orthogonal validation (e.g., fluorescence in situ hybridization or reverse transcription-polymerase chain reaction) for the NGS-detected fusions is a methodological limitation. Finally, the retrospective design and limited follow-up period prevent us from drawing conclusions on long-term survival.

CONCLUSION

This case series provides preliminary evidence that novel FGFR2 fusions could act as potential primary oncogenic drivers in a rare, molecularly distinct subset of wild-type GISTs. Our report highlights the critical value of comprehensive genomic profiling via NGS in identifying such rare, but clinically actionable, mutations. The sustained remission observed in our patients under adjuvant imatinib therapy warrants further investigation into the optimal treatment strategies for this molecular subtype. As precision oncology evolves, our findings suggest that FGFR-targeted therapies might represent a valuable future treatment strategy for managing patients with advanced or recurrent FGFR2-mutated GISTs, meriting further study in larger prospective cohorts.