Discovery of a novel ITPR2::KRAS fusion in large cell neuroendocrine lung cancer: a case report

Abstract

Background

There are many common gene mutations that occur in lung cancers, including KRAS. KRAS is an oncogene responsible for mediating cell growth through the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway. ITPR2 is a calcium channel responsible for regulating intracellular calcium levels. This case report highlights the presence and detection of a previously unreported ITPR2::KRAS fusion in a large cell neuroendocrine carcinoma of the lung.

Case Description

A 65-year-old patient with a history of smoking developed an aggressive large cell neuroendocrine carcinoma (LCNEC) of the lung. This rare tumor subtype (up to 3% incidence in lung cancer) has a particularly poor prognosis, with a median overall survival of 8–12 months. Additionally, the tumor possessed a previously unreported ITPR2::KRAS fusion, which was a unique event upon examining over 100,000 tumors in public databases. Comorbidities including chronic obstructive pulmonary disease (COPD) and neuropathy presented difficulties in the treatment of this patient due to an inability to undergo surgical resection. The patient was successfully treated with concurrent chemoradiotherapy with carboplatin and etoposide, a first-line chemoradiotherapy.

Conclusions

Upon applying relatively unused RNA-fusion tools, this fused ITPR2::KRAS was not projected to yield a functional protein. This supports that post hoc use of bioinformatics tools may support clinical decision-making for patients when encountering rare genomic alterations, captured by existing diagnostic tests, that would be perceived as highly oncogenic.

Highlight box.

Key findings

• A novel ITPR2::KRAS gene fusion that was not observed in >100,000 tumors.

• This patient remains in full remission 24 months post-treatment.

What is known and what is new?

• KRAS is a well-known oncogenic GTPase that contributes to tumor growth. KRAS mutations are common in various cancers, but fusion events are rare. ITPR2 is a calcium channel that regulates intracellular calcium levels.

• This manuscript reports a novel ITPR2::KRAS gene fusion in large cell neuroendocrine carcinoma.

What are the implications, and what should change now?

• Many non-small cell lung cancer patients harbor gene mutations for which targeted therapies are available.

• Utilizing bioinformatics tools may enhance clinical decision-making when encountering rare genomic alterations where the pathogenicity is unclear.

Introduction

Large cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer, accounting for 1–3% of all lung cancers (1). The major risk factor for LCNEC is tobacco smoke, with a previous study showing up to 97.5% of patients are smokers (2). There is limited data showing specific geographical variations in LCNEC incidence; however, in females, the highest rates have been seen in South-East Asia (3). The male-to-female ratio also ranges from 1.4 to 11.1 in North America and Northern Africa, respectively (3). Advancements in molecular profiling have revolutionized the management of non-small cell lung cancer (NSCLC), enabling the identification of driver mutations and the development of targeted therapies (4). Among frequently mutated oncogenes is KRAS, a GTPase that targets the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling pathway, which contributes to tumor growth (5). A majority of KRAS mutations across cancers are single-base missense mutations, located at amino acids G12, G13, and Q61 (5). The most prevalent KRAS mutation in NSCLC patients is G12C which has a targeted treatment via sotorasib (5). However, there are no targeted treatments for KRAS fusions. Furthermore, KRAS fusion events are exceptionally rare at <1% prevalence across all cancers, including lung (6). This case report summarizes the successful management of a patient diagnosed with LCNEC that also harbored a never-reported intrachromosomal ITPR2::KRAS fusion. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1328/rc).

Case presentation

A 65-year-old male former smoker (100 pack-years) was diagnosed with a LCNEC of the lung and had significant pre-existing conditions of chronic obstructive pulmonary disease (COPD) and peripheral neuropathy. The patient has no family history of lung cancer. His mother developed colon cancer at an unknown age. Computed tomography (CT) revealed a 5.0 cm × 6.2 cm solid mass in the right lower lobe, categorized as Lung-RADS 4B (suspicious), and was confirmed by fluorodeoxyglucose positron emission tomography (FDG PET) (Figure 1). A timeline of key diagnostic and therapeutic milestones is provided in Table 1. No prior imaging was available for comparison. Endobronchial ultrasound (EBUS) was negative for adenopathy at stations 7, 4R, and 11R. Biopsy showed high-grade LCNEC, T3N0M0 (stage 2B), which carries a modest to poor prognosis. The tumor was positive for pan-keratin AE1/AE3 and all neuroendocrine markers including INSM1, synaptophysin, and chromogranin, while negative for TTF-1/p40 dual stains, GATA3, SOX10, calretinin, arginase 1, PAX8, CK7, and CK20. Ki-67 proliferation index was elevated at 80%. The PD-L1 score, as determined by the Ventana SP263 PD-L1 assay [Ventana Medical Systems (Roche), Tucson, AZ, USA], was 10%. A tumor sample was sequenced on an Illumina MiSeq instrument (Illumina, San Diego, CA, USA) using the Lung Carcinoma Panel (M Health Fairview Laboratories, Minneapolis, MN, USA), which calculated a tumor mutation burden (TMB) of 34.13 mutations per megabase. No actionable or pathogenic mutations were detected in a panel of 15 oncogenes, including KRAS. The next generation sequencing (NGS) Oncology Pan Tumor Fusion assay from Integrated DNA Technologies (Coralville, IA, USA) was used to screen for fusions across 109 genes, which revealed a previously unreported ITPR2::KRAS fusion. The NGS Oncology Pan Tumor Fusion assay is an RNA-based NGS assay validated for detecting clinically relevant oncogenic fusions in tumors. The assay utilizes anchored multiplex polymerase chain reaction (PCR) chemistry to enable detection of fusion partners across 109 genes, including KRAS, but not ITPR2. This institutionally developed assay is regulated under Clinical Laboratory Improvement Amendments (CLIA) as qualified to perform high-complexity testing for cancer patients. In this study, we acquired the FASTQ files that were processed using the Archer Analysis software. These initial results showcased an ITPR2::KRAS fusion (chr12:26875330, chr12:25398329) which was supported by the analysis from the Arriba workflow that predicts the fusions to be out-of-frame. This fusion joins ITPR2 exon 5 (5' partner) to KRAS exon 2 (3' partner) (chr12:26875330, chr12:25398329). The resulting FASTQ files were then analyzed by the fusion-detection program Arriba, using the GENCODE GRCh37 reference genome and annotation, which supported the presence of the ITPR2::KRAS fusion transcript (Figure 2) (7,8). Arriba detects gene fusions from RNA-seq data by identifying chimeric reads and filtering candidates by sequence content and the number of supporting reads. The ITPR2::KRAS gene fusion candidate was given a high-quality score, but is predicted to be out-of-frame with high confidence (7).

Figure 1.

Fluorodeoxyglucose positron emission tomography image of 5.0 cm × 6.2 cm solid mass in the right lower lobe.

Table 1. Description of timeline of presentation and case progression.

Time point	Clinical event	Details
Age: 64 years (month 0)	Lung cancer screening CT	CT detects a suspicious 5.0 cm × 6.2 cm mass in the RLL
Age: 65 years (month 2)	Endoscopic bronchoscopy with ultrasound	Biopsy shows a high-grade neuroendocrine lung cancer. Lymph nodes are negative for cancer. NGS and fusion studies reveal ITPR2::KRAS fusion
Age: 65 years (month 2)	Clinic visit with Medical Oncology	Medical Oncology recommends discussion with surgery and radiation specialties
Age: 65 years (month 2)	Thoracic Tumor Board	Multi-disciplinary discussion recommends chemotherapy for 2 cycles followed by chemoradiotherapy
Age: 65 years (month 2)	Chemotherapy	Patient starts chemotherapy with carboplatin and etoposide
Age: 65 years (month 4)	Radiation therapy and chemotherapy	Patient completed 2 cycles of chemotherapy. Begins concurrent chemoradiotherapy
Age: 65 years (month 6)	Clinic visit with Medical Oncology	CT scan shows complete response
Age: 67 years (month 24)	Clinic visit with Medical Oncology	CT scan shows continued complete remission

CT, computed tomography; NGS, next generation sequencing; RLL, right lower lobe.

Figure 2.

Arriba predicted ITPR2::KRAS fusion and prevalence in cancer. ITPR2::KRAS fusion plot generated by Arriba. Retained protein domains for ITPR2::KRAS fusion. Prevalence of ITPR2 and KRAS mutations in TCGA Pan Cancer Atlas studies provided by the cBioPortal database. Prevalence of ITPR2 and KRAS mutations within the curated set of non-redundant studies in the cBioPortal database. TCGA, The Cancer Genome Atlas.

To manage the patient, the Thoracic Tumor Board initially recommended surgery if lymph nodes were confirmed negative, but evaluation with pulmonary function tests revealed impaired capacity to undergo surgery. Definitive chemotherapy and radiation were then recommended. Considering both the high proliferation index and the presence of neuroendocrine features, therapy with carboplatin and etoposide was recommended. The patient received carboplatin (area under the curve of 5) on day 1, and etoposide (80 mg/m²) on days 1, 2, and 3 for four cycles with concurrent radiation with the third and fourth cycles of therapy. Radiation was delayed until cycles 3 and 4 due to concerns regarding the potential size of the initial radiation field. Given the high-grade neuroendocrine pathology and the presence of this novel fusion, a schedule of close monitoring, including both frequent body scanning and brain magnetic resonance imaging (MRI), was instituted. The patient had a complete response to therapy. Although consolidation with immunotherapy was discussed based on the high TMB status, the patient declined this option. Frequent monitoring for brain metastases was chosen rather than prophylactic cranial radiation after discussion of options with the patient. The patient remains in complete remission as of the date of publication, over 24 months from completion of therapy (Figure 3).

Figure 3.

Post-therapy chest computed tomography showing remission and minimal scarring of right lower lobe.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

KRAS mutations are among the most common oncogenic alterations across multiple solid tumor types, particularly in lung and colorectal cancers, occurring in approximately 22% of all tumor types (9). In lung adenocarcinoma, KRAS mutations are observed in nearly 33% of cases and have also been reported in large-cell neuroendocrine carcinoma of the lung, with prevalence of approximately 9.7% (10,11). The recurrence of KRAS mutations across diverse malignancies supports their role as broadly relevant oncogenic drivers within tissue-agnostic precision oncology frameworks. In contrast, currently KRAS fusions are not validated biomarkers for LCNEC, and should instead be considered a form of genomic alteration through comprehensive molecular testing. Accordingly, caution is warranted when interpreting a diagnostic report indicating a KRAS fusion event, as their biological and clinical significance may differ substantially from canonical activating KRAS mutations.

While oncogenic KRAS mutations are documented and well-studied in NSCLC, the role of ITPR2 is less understood. ITPR2 is a calcium channel located on the endoplasmic reticulum, which regulates intracellular calcium levels (12). A query across multiple cancers within The Cancer Genome Atlas (TCGA) Pan Cancer Atlas Studies (n=10,953) and curated set of non-redundant studies (n=101,480) confirmed the rarity of independent fusion events in either KRAS or ITPR2 (9 and 50 cases, respectively) (Figure 2) (6). Most notably, this is the first report of an ITPR2::KRAS fusion in cancer patients (6).

The ITPR2::KRAS fusion transcript calculated by Arriba joins exon 5 of ITPR2 to exon 2 of KRAS at breakpoints chr12:26875330 and chr12:25398329, respectively (Figure 2), matching the coordinates from the NGS Oncology Pan Tumor Fusion assay. This breakpoint falls within the coding sequence of ITPR2 and the 5'UTR of KRAS, affecting the inositol 1,4,5-trisphosphate/ryanodine receptor domain of ITPR2 and the Ras of the complex proteins domain of KRAS (Figure 2). While this fusion event may suggest the use of MAPK/ERK inhibitors, this bioinformatics analysis indicates that the fused transcript is predicted to be out-of-frame and would yield a non-functional protein. This has projected deleterious effects on KRAS activity and, therefore, on the MAPK/ERK pathway signaling. Altogether, despite initial concerns upon detecting the KRAS fusion, the patient had a favorable treatment outcome.

Conclusions

Despite the aggressive neuroendocrine features of the tumor, our patient ultimately responded to standard chemotherapies and is in complete remission 24 months after treatment. This case is the first report of an ITPR2::KRAS fusion event in any cancer, much less pulmonary LCNEC. The long-term clinical implications of KRAS fusions remain undetermined. Our case study supports the use of informatics tools that assess protein function, as these may enhance clinical decision-making when encountering exceedingly rare events in which the pathogenicity of the alteration is unclear.

Supplementary

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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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.