Case report: identification of ERC1-RET fusion in a patient with pancreatic ductal adenocarcinoma

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type of pancreatic cancer and accounts for approximately 90%. It is a devastating cancer of the digestive system, which is hard to diagnose and treat (1). Approximately 80% of PDAC patients are diagnosed at an advanced stage (2). Therefore, it is urgent to seek out precision therapy based on the genetic alterations of PDAC.

With the increasing application of next-generation sequencing (NGS) in tumors, more and more therapeutic targets have been found in PDAC. For example, patients with PDAC who harbor variations in homologous recombination genes such as BRCA1, BRCA2, PALB2, and so on, usually respond well to poly [adenosine diphosphate (ADP)-ribose] polymerase inhibitors and cisplatin (3). In addition, patients with mismatch repair gene mutations can often gain clinical benefit from immune checkpoint inhibitors (4). Moreover, patients harboring NTRK gene fusion are sensitive to larotrectinib and entrectinib (5). However, these “actionable” genetic mutations only account for a fraction of PDAC. Thus, there is an urgent need to identify more molecular targets.

The proto-oncogene RET encodes a membrane receptor tyrosine kinase (6). Under normal conditions, the RET gene plays a crucial role in kidney and nervous system development (7-10). When aberrantly activated, RET gene can act as an oncogenic driver in a variety of cancer types. The RET gene is abnormally activated mainly through point mutations and chromosomal rearrangements. The latter will generate fusion proteins including the kinase domain of RET. Apart from those 2 ways, the RET gene can also be activated aberrantly by over expression of wild-type RET (10).

Studies have shown that RET fusions retaining kinase domain are oncogenic drivers in 5–10% of sporadic papillary thyroid carcinoma (PTC) and 1–2% of non-small cell lung cancer (NSCLC) (11). Besides, RET gene fusions are also drivers in other tumors such as colorectal cancer, breast cancer, PDAC, and so on, in which they account for <1% of the total cases of each type (6,12). Specifically, according to the investigation by Kato et al, the occurrence rate of RET fusion in PDAC is 0.6% (6).

To date, it has been reported that there are more than 35 partners of RET gene fusions. In PTC, the most frequent partners are the CCDC6 and NCOA4 genes. In NSCLC, the most common partners are KIF5B, CCDC6, and NCOA4 genes (10,13,14).

The ELKS/Rab6-interacting/CAST family member 1 (ERC1) gene is located at 12p13.3, and is ubiquitously expressed (15). Previous studies have reported that its product ERC1/ELKS scaffold protein could promote migration and invasion of tumor cells (16,17).

The ERC1-RET fusion is a rare rearrangement. To date, it has only been reported in lung cancer and thyroid carcinoma (18,19). The study of ERC1-RET fusion in PDAC has not yet been explored.

In this study, an ERC1-RET fusion was detected through NGS and verified by Sanger sequencing in a patient with PDAC. To the best of our knowledge, this case was the first report about ERC1-RET fusion in a patient with PDAC. We present the following case in accordance with the CARE reporting checklist (available at https://dx.doi.org/10.21037/gs-21-469).

Case presentation

The study conformed to the provisions of the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of Shengjing Hospital of China Medical University. 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. A 60-year-old female patient was referred to our hospital on 25 August 2020 due to her skin and sclera having turned yellow for 1 month. She had no abdominal pain, distension, vomiting, or dizziness, but had experienced occasional nausea. In addition, the patient complained of loss of appetite and compromised defecation with clay-colored stool. She had lost about 15 kg over the past month. Abdominal enhanced computed tomography (CT) showed a space-occupying lesion of the pancreatic head and neck (Figure 1). Enhanced magnetic resonance imaging (MRI) indicated that the space-occupying lesion was liable to be malignant. No systematic diagnosis and treatment was given to the patient at that time. On 15 September 2020, the patient underwent the Whipple operation. Her pathological diagnosis was moderately to highly differentiated PDAC (pT3N0M0, Figure 2).

Figure 1 CT images of the patient. Arterial and venous phase CT images in the pancreatic head and neck (red arrow refers to the space-occupying lesion). CT, computed tomography.

Figure 2 Pathological findings of the patient. Pathological findings confirmed the space-occupying lesion was PDAC (HE, ×200). PDAC, pancreatic ductal adenocarcinoma.

In order to seek personalized treatment options, paraffin-embedded samples from surgical resection of PDAC in the patient were subjected to NGS through a 599-gene panel [ChosenOne599, ChosenMed Technology (Beijing) Co. Ltd, Beijing, China] on 15 September 2020. The NGS data analysis revealed that the patient harbored an ERC1-RET fusion, and the allele frequency was 5.07%. This fusion included exons 1–16 of ERC1 on chromosome 12 and exons 12–20 of RET on chromosome 10, which retained the complete kinase domain of RET (Figure 3A,3B and Table 1).

Figure 3 ERC1-RET fusion was identified by NGS and verified through Sanger sequencing. (A) Sequencing reads of ERC1-RET fusion were shown by IGV; (B) Schematic diagram of ERC1-RET fusion; (C) ERC1-RET fusion was verified by Sanger sequencing. NGS, next-generation sequencing; IGV, Integrative Genomics Viewer.

Sequencing reads of ERC1-RET fusion were shown by the Integrative Genome Viewer (IGV) in Figure 3A. Somatic mutations in the patient are demonstrated in Table 1.

Sanger sequencing was carried out to verify the ERC1-RET fusion using the same tumor samples from the patient (Tsingke Biotechnology Co., Ltd, Tianjin, China). The results of Sanger sequencing confirmed that the patient harbored the fusion (Figure 3C).

The timeline in the patient is shown in Figure 4.

Figure 4 Timeline of the patient.

Discussion

In this case, the chimeric ERC1-RET protein contains complete kinase domain encoded by RET exons 12–20 and coiled-coil domain encoded by ERC1 exons 1–16, which might activate the downstream signaling pathways and drive oncogenesis (12).

To the best of our knowledge, this case was the first study of ERC1-RET fusion in a patient with PDAC.

New targeted drugs for RET fusion are emerging in succession. In the past decade, the FDA has approved multikinase inhibitors (MKIs) with ancillary RET inhibitor activity such as cabozantinib and vandetanib to treat medullary thyroid cancer, cabozantinib to treat renal cell cancer and hepatocellular carcinoma, lenvatinib to treat thyroid cancer and renal cell cancer, and so on. Recently, with FDA-approved potent and highly selective RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667), precision treatment of RET-positive NSCLC and thyroid cancer has reached a new stage. Moreover, previous studies have indicated that therapeutic efficacy of these inhibitors might depend on RET fusion partners and variants. For instance, Drilon et al. evaluated the clinical response of patients with lung cancer who received treatment with cabozantinib. Their results confirmed that responses occurred in 20% of patients (3/15) harboring KIF5B-RET fusion; however, no clinical benefit was observed in patients harboring CCDC6-RET or ERC1-RET fusion (18).

Although RET fusion is a rare mutation in PDAC, the number of patients with PDAC in China is much higher than that in other countries due to the large population. It is suggested that patients with PDAC should be tested by NGS if possible. If RET fusion is detected, patients will have more treatment options and more chances of survival.

Thus, although no targeted drug has been approved for RET fusion-positive PDAC, PDAC will be diagnosed and treated more accurately in the future based on the increasing application of NGS detection technology.

Our study had presented a new molecular target for the treatment of PDAC. The limitation of the study was that the participant refused to receive inhibitors of RET due to personal reasons.

Conclusions

In summary, this case firstly reported an ERC1-RET fusion in a patient with PDAC. Our study discovered a novel molecular target and has provided clues for the application of RET protein-tyrosine kinase inhibitors in patients with PDAC.

Acknowledgments

The authors wish to thank the patient and all personnel for participating in this study.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/gs-21-469

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-469). EM is an employee of ChosenMed Technology. 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 conformed to the provisions of the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of Shengjing Hospital of China Medical University. 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.

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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(English Language Editor: J. Jones)