01

The Role of Gene Fusion inLung Cancer

Gene fusion refers to theformation of a new hybrid gene by connecting parts or all sequences of twodifferent genes. The fusion protein encoded by it can mediate the occurrenceand development of tumors. In non-small cell lung cancer (NSCLC), gene fusion,as an important molecular mutation, is an ideal target for targeted therapy.Therefore, precise detection of gene fusion in NSCLC is crucial for screeningpatients who can benefit from corresponding targeted therapies.

02

Background of Thymic Tumors

Thymic tumors are a relativelyrare type of tumor, typically located in the anterior mediastinum. They areclassified by the World Health Organization (WHO) pathology classification intothymic epithelial tumors, with an incidence rate of 1.3 to 3.2 per million. In2021, WHO classified thymic epithelial tumors into types A, AB, B1, B2, and B3,to a certain extent reflecting the biological behavior and prognosis of thetumors.

▲The 2021 WHO Classification

03

The Role of Gene Fusions inThymic Epithelial Tumors

This article provides a reviewof gene fusions in Thymic Epithelial Tumors (TET) and outlines their importancein the diagnosis and pathogenesis of TET. While they are not currently used astherapeutic targets, potential treatment options and investigative research areunder discussion. The table below summarizes identified gene fusions in TET,including the frequency of gene fusions, morphological characteristics oftumors, and other diagnostic features.

▲Morphological and diagnosticfeatures of gene fusions in thymic epithelial tumors^[3]

04

MAML2 Rearrangement

In the thymus, MAML2rearrangement was first discovered in mucoepidermoid carcinoma. Subsequently,they were also found in suppurative thymoma and rare B2 and B3 thymomas.Despite common MAML2 fusion partners, the corresponding fusion genes varydepending on the tumor subtype in which they occur. In a study of 20 cases ofthymic mucoepidermoid carcinoma, 56% had t(11;19) (q21;p13) CRTC1::MAML2 genefusion. Additionally, CRTC3::MAML2 or EWSR1::POU5F1 fusions were observed.Furthermore, YAP1 and KMT2A were not identified as fusion partners in thymicmucoepidermoid carcinoma. Interestingly, the presence of CRTC1::MAML2 genefusion in thymic mucoepidermoid carcinoma is associated with typical histology,lower pT and TNM staging, and better prognosis.

In thymic tumors, MAML2rearrangement aids in diagnosis, particularly in mucoepidermoid carcinoma.Currently, there are no therapeutic targets for MAML2 rearrangement, but thesestudies have also revealed that EGFR and CDK4/6 inhibitors are potential therapeuticoptions for these tumors.

05

EWSR1 Rearrangement

Epithelial-myoepithelialcarcinoma (EMC) with EWSR1 rearrangement can occur in the thymus and has beenincluded in the 2021 WHO classification. It has been reported that thymic EMCcases showed EWSR1 rearrangement, with one case showing fusion of exon 13 ofEWSR1 with exon 6 of ATF1. Indeed, reports have indicated that ATF1 is the mostcommon fusion partner of EWSR1 in EMC in other organs, but there are fewreports of CREM with or without IRF2::NTRK3 fusion.

06

NTRK Rearrangement

Chromosomal rearrangements ofneurotrophic receptor tyrosine kinase (NTRK) are found in only 0.3% of solidtumors. This article reports a rare thymic tumor with NTRK fusion. A50-year-old male patient underwent lung mass biopsy suggesting thymic tumor, indicatingB3 type. The patient was clinically diagnosed with stage IV. NGS revealedEIF4B::NTRK3 rearrangement, and subsequently, the patient received treatmentwith entrectinib, a selective tyrosine kinase inhibitor for TRKA, B, C, ALK,and ROS1.

Recurrent gene rearrangementsare found in various types of thymic epithelial tumors (TETs). Although rare,they may provide opportunities for targeted therapy. For certain tumors, thesegene rearrangements may offer opportunities for future targeted therapy.Molecular studies of these rare tumors need to be expanded inmulti-institutional global research to provide personalized targeted therapyand management for patients with sometimes quite aggressive tumors.

Note: Not all rearranged genesmentioned in the literature are excerpted here.

07

Treatment of Thymic EpithelialTumors

The CAP regimen can be used asthe preferred first-line chemotherapy for thymic tumors.

Summary

1. Gene fusion mainly occursthrough chromosome structural rearrangements, including common mechanisms suchas inversion, translocation, insertion, deletion, tandem duplication,chromosome fragmentation, etc., resulting in gene fusion at the DNA level.Second-generation sequencing can detect gene fusion at the DNA or RNA level.Through large-scale parallel sequencing methods, multiple fusion genes withinthe range of primer or probe design can be detected simultaneously.

2. Based on current researchon gene fusion in lung cancer, targeted therapy for fusion genes has progressedrapidly, bringing significant clinical benefits to patients with specificfusion gene positivity. Therefore, the application of gene fusion detection indifferent solid tumors is expected to yield more new discoveries in futureresearch.

References:

1. Eur J Cancer, 2008, 44(1):123-130. DOI: 10.1016/j.ejca.2007.11.004.

2.https://doi.org/10.1016/j.jtho.2021.10.010

3. Gene Fusions in ThymicEpithelial Tumors. Cancers 2023, 15, 5596.

4. Am. J. Surg. Pathol. 2022,46, 1160–1169.

5. Histopathology 2019, 75,431–436.

6. Front. Oncol. 2023, 13,1175279

7. Salame, H.; McKey, R.;Ballout, M.; Saad, W. The First Reported Case of Neurotrophic Tyrosine ReceptorKinase Fusion-Positive Thymoma Treated Successfully With Entrectinib. Cureus2021, 13, e20588.

8. Clinical Diagnosis andTreatment Guidelines for Thymic Epithelial Tumors in China (2021 edition)

9. Chinese Expert Consensus onClinical Practice of Fusion Gene Detection in Non-Small Cell Lung Cancer (2023edition)

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