Histopathologic, molecular, and clinical associations of fusion-positive gastrointestinal carcinomas

Introduction

Gastrointestinal (GI) carcinomas are collectively the most common cancers in the United States with an estimated 369,970 cases in 2026 and cause the greatest number of deaths annually (1). These include cancers along the GI tract from the esophagus to the anus as well as hepatobiliary and pancreatic cancers. Adenocarcinoma histology is most common; however, squamous, neuroendocrine and other histologies are also seen. Despite some commonalities, treatment of each cancer is personalized based on the anatomic location, stage, histology, and, increasingly, molecular features.

Comprehensive genomic profiling (CGP) is essential in many GI carcinomas to appropriately select treatment. These treatments include therapies targeting BRAF, HER2, and EGFR in colorectal cancer (CRC) (2-6), HER2 and Claudin18.2 in esophagogastric adenocarcinoma (EGA) (7,8), FGFR2 fusions in biliary tract cancers (BTCs) (9), and now KRAS across many cancer types, especially pancreatic cancer (10). Outside of BTCs, actionable fusions in GI carcinomas are uncommon; however, when identified can transform a patient’s clinical course. These rare fusions include NTRK1-3 (11), NRG1 (12,13), MET (14,15), and RET (16), as well as FGFR fusions identified outside of BTCs. However, the utility of comprehensive fusion testing is not well established in these cancers, as most fusions are individually rare.

Biologically relevant fusions without established targeted therapy have also been regularly reported in GI cancers including RSPO2/3 and BRAF fusions. RSPO2/3 fusions are the most common fusions identified in CRC and lead to activation of the Wnt/beta-catenin pathway (17). These fusions have a distinct molecular pattern in CRC, including wild-type (WT) APC and frequently co-mutated RAS/BRAF V600E. They are thought to arise during CRC oncogenesis via the serrated neoplasia pathway, in which a RAS or BRAF mutation is the first event, rather than the more common conventional adenoma pathway, in which APC mutations are the first event (18-21). Unfortunately, attempts to target RSPO2/3 using novel agents have been unsuccessful and this population remains relatively poorly characterized. BRAF fusions are seen across GI cancers (22), leading to activation of the MAPK pathway and resistance to other MAPK-targeted therapies. These fusions are unfortunately not themselves susceptible to currently available BRAF inhibitors, although molecules currently in development may also target BRAF fusions.

At our institution, CGP has been performed with a combined DNA- and RNA-based next-generation sequencing (NGS) approach. While DNA-based NGS assays specifically designed to detect rearrangements can detect oncogenic fusions through tiling of introns through hybrid-capture, there are limitations. They rely on a priori knowledge of known introns and larger introns with repetitive elements present technical challenges that can lead to false negatives. RNA-based fusion assays provide direct evidence of a functional mRNA transcript and have been shown to be more sensitive, especially at detecting non-canonical fusions (23-25). However, large-scale studies with RNA-based fusion NGS have been relatively lacking in GI cancers. Therefore, with our ample clinical genomic data, we investigated the landscape of fusions in GI carcinomas seen at our institution to assess the utility and outcomes of fusion testing in this population. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0178/rc).

Methods

Patient selection

Patients at Massachusetts General Brigham Cancer Institute (MGBCI) who underwent internal fusion testing on tumor tissue with an associated diagnosis of any GI carcinoma between January 2016 and April 2022 were identified. These cutoff dates were selected to maintain homogeneity given changes in fusion testing after this date. Only patients whose testing met quality control metrics, such as a minimum tumor cellularity of 20%, were included. Patients with non-carcinomas, such as GI stromal tumors, were excluded. The small number of patients with a diagnosis of carcinoma of unknown primary (CUP) were manually reviewed to identify patients of likely or definite GI primary based on histopathologic characterization, imaging, and treating physician’s best judgment. Tumors not felt to be of GI origin were excluded.

An additional cohort of RSPO fusion mutated cancers identified after April 2022 were included for the RSPO fusion specific analyses only. These additional patients are not included in the frequency analyses across cancer types. Patients with BRAF V600E mutated CRC were identified from patients who underwent SNAPSHOT-NGS concurrently with fusion testing on tumor tissue at MGBCI.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Dana Farber/Harvard Cancer Consortium institutional review board (No. 24-154). The protocol was considered exempt from informed consent because the study was non-interventional, de-identified, and retrospective.

Molecular testing

Both the Solid Fusion and SNAPSHOT-NGS assays were developed by the MGH Center for Integrated Diagnostics for internal use at MGBCI.

Solid Fusion Assay is an RNA-based assay designed for gene fusion detection and SNAPSHOT-NGS is DNA-based for detection of single-nucleotide variants (SNVs), insertions/deletions (indels), and copy number variants (CNVs). They utilize anchored multiplex PCR (AMP) for targeted variant detection using NGS (Archer Dx, Boulder, CO, USA) (26). Total nucleic acid is isolated from a formalin-fixed paraffin-embedded tumor specimen after histological review for tumor enrichment. For fusion detection, total nucleic acid is then reverse transcribed, followed by second-strand synthesis to create double-stranded complementary DNA (cDNA). Half-functional adaptors were ligated, and the adaptor-ligated DNA or cDNA was amplified in two hemi-nested PCR reactions using gene-specific primers. The amplicons were sequenced with an Illumina NextSeq 500/550 (Illumina, San Diego, CA, USA). Sequencing results were aligned to the human reference genome (hg19) and analyzed using either a laboratory-developed algorithm or Archer Analysis (ArcherDx, Boulder, CO, USA) for detection and annotation for reporting. Included genes in the solid fusion assay are listed in Table S1.

The assay is validated for samples showing 5% or higher tumor cellularity; however, for the purposes of this study, a cellularity cutoff of 20% or higher was applied.

Data and statistical analyses

Clinical data for all patients who were fusion positive were extracted via retrospective chart review into Excel. Prism GraphPad was utilized for Kaplan-Meier survival analysis for all patients, and the log-rank test was applied to assess for statistical difference in survival. Survival was considered from any case calculated from first detection of metastatic disease, while time on treatment was calculated from the onset of treatment to completion of a treatment cycle. Patients were censored at last known follow-up. Non-metastatic patients were not included in survival or treatment analysis.

Results

Fusions detected across cancer types

A total of 2,300 patients with GI carcinomas who underwent fusion testing and otherwise met criteria were included for analysis. Of these, 139 (6.0%) had a fusion detected (Table 1). Fusion detection ranged from 0–13.7% across different cancer types. BTCs unsurprisingly most frequently harbored fusions (13.7%), primarily with FGFR2. No fusions were detected among 47 GI neuroendocrine cancers. Potentially actionable fusions involving BRAF (0.5%), FGFR1–3 (2.4%), NTRK1–3 (0.3%), and NRG1 (0.2%) were detected across 3 or more cancer types; MET fusions were detected in BTC and CRC, CLDN18 fusions in pancreatic ductal adenocarcinoma (PDAC) and EGA, and 2 RET fusions in CRC. While individually rare (<0.5%) outside of FGFR2 in BTC, potentially actionable fusions were cumulatively detected in 2.8% of pancreatic tumors, 1.5% of CRC, and 3.5% of EGA. RSPO2/3 fusions were also detected relatively frequently, especially in CRC (2.5%), but are not yet considered actionable.

Characterization of RSPO2/3 fusions in lower GI cancers

Given the frequency of RSPO2/3 fusions in CRC and other intestinal-type cancers [small bowel adenocarcinoma (SBA) and appendiceal carcinoma (APP)], we next explored the clinical and histopathologic associations of RSPO2/3 fusions in these populations. Among patients with RSPO2/3 mutated CRC, 58.6% were male and 79.3% were white in our cohort (Table 2). 62% of patients had left sided CRC, similar to that expected from a normal distribution of CRC(27). Metastatic sites at diagnosis were also typical for CRC, including 51.7% with liver metastases, 37.9% with peritoneal metastases, and 34.5% with pulmonary metastases. 44.8% of CRC patients demonstrated some mucinous histology and 27.5% were grade 3, while 4 of 5 (80%) of the SBA and APP identified were grade 3 with mucinous histology.

Histologic and molecular characterizations of RSPO2/3 fusions in CRC, SBA, and APP are shown in Figure 1. 100% of patients with RSPO2/3 fusions were mismatch repair proficient (pMMR)/microsatellite stable (MSS). RSPO3 fusions were exclusively observed partnered with PTPRK, while the sole RSPO2 fusion partner was EIF3E. As previously described, RSPO fusions were predominantly associated with KRAS (38.2%) or BRAF V600E (44.1%) mutations and were largely APC WT (94.1%). Twenty-six of 29 CRC (89.7%) harbored either a KRAS or BRAF V600E mutation. Of the 6 patients without KRAS or BRAF V600E mutations, 3 were SBA or APP; 2 SBA had non-V600 BRAF mutations and 1 CRC harbored a RET fusion as well, which to our knowledge has not previously been described. Mutations in TP53 (76.5%) and SMAD4 (26.5%) were slightly more frequent than expected compared to the literature (28).

Figure 1 Molecular and histologic associations of RSPO2/3 fusions in colorectal, small bowel, and appendiceal carcinomas. Individual patients with RSPO fusions are shown in each column, with associated molecular and histologic findings. Only mutations that occurred in 2 or more patients or were of special interest are shown. Percentage of patients with a specific alteration is shown. APP, appendiceal cancer; CRC, colorectal cancer; MSS, microsatellite stable; SBA, small bowel adenocarcinoma.

RAS and BRAF mutations are known to predict worse prognosis compared with RAS/RAF WT CRC. We therefore examined clinical outcomes for RSPO fusion mutated CRC based on the presence of a co-mutation with KRAS or BRAF V600E versus WT. For those patients who received systemic therapy for metastatic disease, all of whom received 1^st line fluoropyrimidine based chemotherapy, there was no significant difference in time on first-line therapy between patients with BRAF V600E mutated (27 weeks), KRAS mutated (20 weeks), or WT (28 weeks) (Figure 2A). However, patients with BRAF V600E mutations demonstrated significantly worse median overall survival (mOS; 1.05 years) compared to WT (mOS 5.63 years, P=0.03) (Figure 2B). Patients with KRAS mutations showed numerically intermediate mOS of 2.06 years compared with patients who were BRAF V600E mutated (P=0.14) or WT (P=0.24); however, this difference did not reach statistical significance. Although this analysis is significantly limited by patient number, the numerical difference in survival is similar to the differential prognosis predicted by the presence of KRAS and BRAF V600E mutations in CRC (29,30).

Figure 2 Clinical outcomes for patients with RSPO fusions. (A) Kaplan-Meier curve of time on first line therapy for patients with CRC, SBA, or APP cancers with RSPO2/3 fusions. All patients received fluoropyrimidine based chemotherapy in the first line. Median time on therapy is shown in the legend in weeks; no statistically significant difference was observed by log-rank test. (B) Kaplan-Meier curve of OS from first diagnosis of metastatic disease for patients with CRC, SBA, or APP cancers with RSPO2/3 fusions. Median OS is shown in the legend. A statistically significant difference in median OS was shown between BRAF V600E and WT by log rank test; no statistically significant difference was observed between other groups. (C-E) OS from first diagnosis of metastatic disease for patients with BRAF V600E mutated CRC, stratified by ever receipt of targeted therapy (tx) in RSPO2/3 co-mutated CRC (C), presence or absence of an RSPO2/3 fusion in patients who ever received targeted therapy (D), or presence or absence of RSPO2/3 fusion in patients who never received targeted therapy (E). Median OS is shown in the legend. No statistically significant difference was noted by log-rank test for any comparison. APP, appendiceal cancer; CRC, colorectal cancer; ns, not significant; OS, overall survival; SBA, small bowel adenocarcinoma; WT, wild type.

BRAF V600E mutations are present in 5–10% of metastatic CRC and BRAF V600E targeted therapies prolong survival in these patients (2,3). However, whether RSPO fusions modify response to BRAF targeted treatment is unknown. We therefore compared overall survival (OS) of CRC patients with and without RSPO2/3 fusions who ever received targeted therapy against BRAF V600E, as well as patients who never received BRAF targeted therapy during their disease course (Figure 2C-2E). RSPO/BRAF V600E-commutated CRC demonstrated numerically longer mOS with anti-BRAF targeted therapy (2.15 years) compared to without therapy (0.80 years); however, this difference did not reach statistical significance (Figure 2C, P=0.12). There was also no significant difference in mOS by presence of RSPO fusion in either patients receiving targeted therapy (Figure 2D, P=0.21) or patients who never received anti-BRAF therapy during their course (Figure 2E, P=0.48).

Non-RSPO Fusions in CRC, SBA, and anal cancer

We also examined the clinical and molecular associations of non-RSPO fusions in CRC as well as a single SBA and anal cancer (Figure 3). These fusions were heterogeneous, including BRAF, FGFR3, NTRK1 or NTRK3, RET, MET, and several fusions of unclear biologic significance. Overall, nearly all fusions were associated with either TP53 mutations (66.7%) or microsatellite instability-high (MSI-H) (22.2%), which may be associated with genomic instability. All 3 NTRK1 fusions were associated with MSI-H, consistent with previous reports (31). 4 CRC patients were also KRAS mutated; of these, only 1 fusion (FGFR3::TACC3) would be considered a driver fusion but as this is rarely seen in CRC, its significance is unclear. The solitary TRA2A::MET fusion was novel but predicted actionable; this patient had a mixed response to off-label MET targeted therapy. The only fusion detected in anal cancer in our cohort, INO80D::MAST2, was of unclear biologic significance.

Figure 3 Molecular and histologic associations of fusions (excluding RSPO) in colorectal, small bowel, and appendiceal carcinomas. Individual patients with fusions are shown in each column, with associated molecular and histologic findings. AD, adenocarcinoma; CRC, colorectal cancer; MSI-H, microsatellite instability-high; MSS, microsatellite stable; SBA, small bowel adenocarcinoma; SCC, squamous cell carcinoma.

Fusions detected in pancreatic cancers

We then examined molecular and histologic associations of detected fusions in pancreatic cancers (Figure 4A). As previously described, most detected fusions occurred in patients who were KRAS WT (75%), in contrast to most pancreatic cancers in which 85–90% are KRAS mutated (15,32). Of the 5 patients with KRAS mutations, 3 of 5 had detected FGFR2 or FGFR1 fusions. A novel ITPR2::ETV6 fusion was only detected on one of two assays completed on this patient and was of uncertain clinical or biologic significance. In addition, 4 of 5 (80%) KRAS mutated patients were TP53 mutated and all displayed adenocarcinoma histology, consistent with the most common patterns of pancreatic cancers. Of the 15 KRAS WT patients, 4 had either acinar cell or oncocytic histology, rather than adenocarcinoma. All fusions detected in these KRAS WT cancers were biologically relevant and potentially actionable fusions, involving CLDN18, FGFR2, BRAF, NTRK1/3, EGFR, and NRG1. Three fusions in the KRAS WT group were novel, including an EGFR::SEL1L fusion, FGFR2::LRRFIP2, and FGFR2::TUFT1. Relatively few patients were TP53 (27%) or SMAD4 (0%) mutated, in contrast with more typical pancreatic cancer, further highlighting the distinct molecular characteristics of this population.

Figure 4 Characterization of pancreatic carcinomas with fusions. (A) Individual patients with fusions are shown in each column, with associated molecular and histologic findings. Only mutations that occurred in 2 or more patients are shown, with percentage of specific alterations shown in the left column. Receipt of targeted therapy (tx) against the detected fusion is also shown and includes zenocotuzumab, erlotinib, entrectinib, larotrectinib, and pemigatinib. (B) OS of patients with KRAS WT, fusion positive pancreatic carcinomas ever treated with or without fusion targeted therapy (tx). Median OS is shown in the legend. A statistically significant difference in median OS was shown by log rank test. AC, acinar cell carcinoma; AD, adenocarcinoma; MSS, microsatellite stable; Onc, oncocytic carcinoma; OS, overall survival; WT, wild type.

Six of 15 (40%) KRAS WT pancreatic cancer patients received targeted therapy against their fusion during their disease course. We compared overall survival of these patients to those with fusions who never received targeted therapy (Figure 4B). The mOS was 3.99 years for those who ever received targeted therapy, compared with only 0.63 years for those who never received targeted therapy (P=0.001). This finding is subject to potential confounding, including biologic differences between fusions with and without readily available inhibitors and eligibility for therapy based on clinical status, as well as small patient numbers. However, the marked difference in survival highlights the potential for improved clinical outcomes for patients who can access targeted treatments.

Fusions detected in esophagogastric cancers

In total, 20 of 346 (5.8%) EGA patients harbored a fusion (Table 1). Overall, these fusions were heterogeneous, including 5 FGFR1–3, 4 RSPO2, 4 CLDN18, and 1 NRG1 fusion (Figure 5). All tumors were adenocarcinoma and MSS. Copy number alterations (CNAs) were only observed in patients with TP53 mutations, consistent with chromosomal instability. However, 3 of 4 CLDN18 fusions were observed in the minority of patients who were TP53 WT and with no CNA, all gastric cancers, consistent with prior reports that these fusions and CLAUDN18.2 expression are more common in genomically stable gastric cancer (33). The small sample size limited further characterization.

Figure 5 Molecular and histologic associations of fusions in esophagogastric carcinomas. Individual patients with fusions are shown in each column, with associated molecular and histologic findings. AD, adenocarcinoma; ESO, esophagus; GAS, gastric; GEJ, gastroesophageal junction; MSS, microsatellite stable.

Fusions detected in BTCs

Finally, we examined fusions detected in BTCs. The 42 FGFR2 fusions in BTC were by far the most common fusions in BTCs (77.8%) and in the whole dataset (30.2%). As previously described, 100% of FGFR2-fusions were intrahepatic cholangiocarcinoma (ICC) and MSS, as was the solitary FGFR3 fusion (Figure 6A). An additional single FGFR1 fusion in an extrahepatic cholangiocarcinoma (ECC) was also observed. FGFR2 fusions had heterogeneous molecular associations. There was little overlap with other known targetable mutations in BTC, including IDH1 (1 of 42, 2.4%), ERBB2 amplification (1 of 42, 2.4%), and KRAS (0 of 42, 0%). 16.7% of FGFR2-fusion altered BTC carried an ARID1A mutation, while no ARID1A mutations were observed in BTC patients with non-FGFR2 fusions.

Figure 6 Characterization of biliary tract cancers with fusions. (A) Individual patients with fusions are shown in each column, with associated molecular and histologic findings. FGFR2 fusions are coded green and MET fusions yellow. Fusions were only observed in intrahepatic and extrahepatic CC; no fusions in gallbladder or ampullary cancers were identified. (B) Overall survival of patients with FGFR2-fusion positive cholangiocarcinoma ever or never treated with fusion targeted therapy (tx). Median OS is shown in the legend. A statistically significant difference in median OS was shown by log rank test. BTC, biliary tract cancer; CC, cholangiocarcinoma; MSI-H, microsatellite instability-high; MSS, microsatellite stable; OS, overall survival.

Four BTC patients with MET-fusions were identified; of these 4 (100%) were in ICC and 3 (75%) were high grade with mutations in TERT. Individual fusions with BRAF and NRG1 of possible clinical significance were noted, while remaining fusions were of unclear significance. No fusions were detected in patients with gallbladder or ampullary primaries.

Finally, not all patients with FGFR2 fusions were able to receive targeted therapy, likely due primarily to diagnosis prior to widespread availability of FGFR2 inhibitors. Given this, we examined overall survival of patients who were able to receive FGFR2 inhibitors during their disease course, compared to those who did not (Figure 6B). OS was significantly improved in those patients who ever received an FGFR2 targeted therapy (mOS 2.77 years), compared with those who did not (0.79 years, P=0.01), highlighting the importance of identifying these patients and ensuring access to appropriate targeted therapy.

Discussion

Our study demonstrates the potential for routine RNA-based fusion testing across GI cancers. In total, 6% of our 2,300 patients with GI carcinomas harbored fusions. Biologically relevant and potentially actionable fusions were identified at clinically significant rates across GI carcinomas, including >1% of BTC, CRC, pancreatic cancers, EGA, and SBA. Fusions in FGFR2, BRAF, NTRK1/3, RET, NRG1, MET, and CLDN18 were detected across multiple cancer types. When identified, these patients have the potential for a marked change in clinical outcome given high response rates associated with targeted therapy. Biologically relevant RSPO2/3 fusions were also detected relatively frequently, especially in CRC and SBA; these fusions are not yet considered clinically actionable but could be targeted by future investigational agents. Therefore, routine and comprehensive fusion testing is indicated for these common GI cancers.

RSPO2/3 fusions, primarily RSPO3, are the most common biologically relevant fusions identified in CRC and SBA. We observed that these fusions have a distinct molecular pattern, with nearly all patients either KRAS or BRAF V600E co-mutated as well as APC WT, consistent with prior studies (18,20). 1 patient had a co-occurring RET fusion, which, to our knowledge, has never previously been reported but may occupy a similar biologic role to a KRAS or BRAF mutation. Survival of RSPO fusion mutated CRC appears to stratify as expected by RAS/RAF status, with WT patients having the best prognosis, KRAS intermediate, and BRAF V600E the worst. However, there was no significant difference in time on first-line therapy, a proxy for progression-free survival, stratified by RAS/RAF status in the RSPO mutated cohort.

Our cohort is partially drawn from an era prior to the widespread availability of BRAF targeted therapy. We therefore compared the survival of RSPO2/3-fusion, BRAF V600E co-mutated patients who received BRAF targeted therapy to those who did not, as well as to non-RSPO2/3 BRAF V600E mutated CRC who did and did not receive targeted therapy. Patients who received targeted therapy had numerically superior OS compared to those who did not, regardless of RSPO status, suggesting at least that RSPO fusions do not confer resistance to anti-BRAF therapy, a finding which has not to our knowledge been previously evaluated. Interestingly, mutations in RNF43, a negative regulator of WNT signaling, do appear to predict greater benefit from BRAF targeted therapy in BRAF V600E mutated CRC (34). Given a potentially similar WNT activating phenotype, further investigation into RSPO fusions as a predictor of response to BRAF targeted therapy is warranted.

Pancreatic cancer that is KRAS WT has previously been shown to have distinct molecular and histologic patterns from the most typical PDAC, often harboring fusions (15,32). Here we confirm that receipt of targeted therapies against the fusion protein is associated with longer survival. Some patients may not receive therapy due to clinically advanced disease; therefore, early identification of these patients to allow treatment may improve outcomes. The 5 patients in the pancreatic cohort with BRAF fusions lack a Food and Drug Administration (FDA)-approved option for targeted therapy, but several molecules under development could improve outcomes for these and the several other BRAF fusion-positive cancers identified in our study. For FGFR2 mutated BTC, receipt of FGFR2 targeted therapy was also associated with improved OS, unsurprisingly given FGFR inhibitors such as pemigatinib and futibatinib are well known to improve survival in these patients.

EGA with fusions were heterogeneous. CLAUDN18 fusions may be targetable (although indications for current Claudin18.2 targeting therapies are based on protein expression rather than genomic alterations). These did appear to occur in TP53 WT gastric cancers, consistent with prior reports that Claudin18.2 overexpression is more often associated with less genomically complex gastric cancers (33). FGFR2, RSPO2, and NRG1 fusions were also observed.

Finally, several fusions with novel partners were identified and predicted actionable in our dataset. These findings highlight the benefits of partner-agnostic RNA-based fusion testing, which may identify novel partners or complex or unusual breakpoints that result in clinically actionable fusions.

Our findings are subject to several critical limitations. This is a single-institution study based on an internally developed proprietary assay and all findings require validation in broader patient populations. Only 1 fusion was detected in HCC, while no fusions of clinical significance were detected in GI NET, CUP of suspected GI primary, anal, and appendiceal cancers; evaluation of these cancers was limited by small patient numbers. Whether fusions are frequent enough in these cancers to justify routine testing cannot be determined from our data. Nearly all patient subgroups were small and clinically heterogeneous, in addition to experiencing differing standard of care and clinical trial access depending on time of diagnosis. Survival analyses examining receipt of targeted therapy are especially subject to confounding such as selection and survival bias towards patients who underwent fusion testing or who were eligible to receive targeted therapy, especially on clinical trials. Larger prospective studies are required to validate any observed differences.

Conclusions

CGP using RNA-based fusion testing identified distinct molecular patterns in GI cancers. Many of these patterns have previously been described and are confirmed here. We find that actionable fusions are detected at a clinically significant rate in the most common GI cancers and that therapy targeted to the fusion protein may improve clinical outcomes. Fusion testing will become increasingly important as new targeted therapies become available, for example against BRAF or RSPO fusions, or as new combinations become available. Together, these data support the role for systematic, early, and comprehensive fusion testing in GI cancers.

Acknowledgments

A previous version of this work was presented at the American Society for Clinical Oncology Annual Meeting, Chicago, IL, USA in May, 2024.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0178/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0178/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0178/prf

Funding: This work was supported by Internal departmental funding.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0178/coif). B.A.C. has served on an advisory board for Guardant Health. L.P. has served as an advisor/consultant for Astellas Pharma, Caris Life Sciences, Kestrel Therapeutics, Merus and Tallac Therapeutics. He has received honoraria for events organized by Bristol Myers Squibb Company, Takeda Pharmaceutical Company and Biocartis. He has previously held equity in Eli Lilly & Co and Moderna. V.N. has received consulting fees from Predicta Biosciences and honoraria from Pfizer and ThermoFisher Scientific. A.J.I. has received royalties from IDT/Archer Dx, Consulting fees from AstraZeneca and Intellia; and owns equity in Monimoi Therapeutics. R.B.C. is a co-founder/Scientific Advisory Board/Board of Directors/Equity Holder for Alterome Therapeutics and Sidewinder Therapeutics; he is a scientific advisory board member and equity holder for Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Interline Therapeutics, Kinnate Biopharma, Nested Therapeutics, nRichDx, Remix Therapeutics, and Revolution Medicines; he has received research funding from Invitae, Lilly, Novartis, OnKure, Pfizer, and Relay Therapeutics; he has received ongoing consulting fees from Abbvie, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, Avidity Biosciences, BMS, C4 Therapeutics, Cogent Biosciences, Elicio, Erasca, FOG Pharma, Guardant Health, Ipsen, Kinnate Biopharma, Mirati Therapeutics, Navire, Nested Therapeutics, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roivant, Syndax, Taiho, Tango Therapeutics, and Zikani Therapeutics. C.I.W. has received honoraria from Thermo Fisher Scientific and Roche Pharmaceuticals. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Dana Farber/Harvard Cancer Center institutional review board (No. 24-154). The protocol was considered exempt from informed consent because the study was non-interventional, de-identified, and retrospective.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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