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In non-small cell lung cancer (NSCLC), the fusion mutation and Related, and different fusion mutations show obvious differences in the treatment response, this difference may originate from their respective unique co -conflict. [1].With the rapid development of molecular targeted therapy and personalized medical care, in -depth analysis of the genetic background of these gene mutations is crucial to optimize the treatment of NSCLC.At the ESMO Conference in the European Medicine Institute (ESMO) in 2024, a "Optimising Targeted therapy in NSCLC: A Comprehensive Analysis of oncogenic Fusion Mutations and Co-Mutations LandScapes" ( Summary number: 1277p) Study [2], passed throughThe in -depth genetic analysis of the samples of large -scale NSCLC patients reveals the biological characteristics of different gene fusion mutations and mutations, and provides a strong basis for formulating more effective treatment plans.
Research background
Common drive gene fusion mutations in NSCLC, such as ALK, RET and ROS1, etc.Tightly related to the growth and proliferation of tumor cells.Although targeted therapy has achieved certain effects on these fusion mutations, there are still differences in the treatment response in different fusion types. This difference may be determined by the different tumor mutation load (TMB) and the syndrome.TMB reflects the number of non -velled mutations in tumors, while common mutations refer to other gene mutations that exist at the same time as the main driver mutation, which may affect the sensitivity of tumors to treatment.Therefore, in -depth understanding of the genetic background of different fusion mutations is essential to design a more accurate treatment strategy.
Research Method
This study analyzed 1565 cases passed the second -generation sequencing (NGS) test diagnosis NSCLCSamples of patients with mutations, these samples come from 733 genome/liquid biopsy panel detection.The sample includes 1125 tumor tissue samples and its corresponding blood samples, plus 440 independent blood samples.The TMB is defined as the total number of non -synonymous cells in the coding area.This study compares the comparative analysis of TMBs and its co -variations of different fusion mutations to reveal the genetic differences of different fusion mutations types.
Research Results
Among 1565 NSCLC patients, the patients median age is 42 years, genderThe distribution is uniform; the highest proportion of adenocarcinoma (92%), and 7%and 1%of squamous cell carcinoma and gonadechyloma, respectively.The main fusion mutations include ALK (39.6%), RET (12.8%), ROS1 (9.2%), FGFR1-3 (3.9%), NTRK1-3 (1.79%), NRG1 (1.3%), EGFR and BrafThe mutations were 2.56%and 1.79%, respectively.
TMB differences of different fusion mutations are significantly significantly, the highest TMB of FGFR1-3 (10.82 Muts/MB), and the lowest TMB of NRG1 (3.72 Muts/MB).The total mutation rates of TP53 are different, and the highest (64%-78%) of EGFR, Braf, and FGFR1-3 is low (9%-28%) in ALK and ROS1.
There are also differences in the co -conflict of different fusion types.ALK and ROS1 showed a lower rate of common mutation, mainly mutaged with CDKN2A and CDKN2B.Fusion mutations fusion of FGFR1-3, NTRK1-3 and Braf often mutations with EGFR and PIK3CA, suggesting that they are similar to EGFR secondary mutations.RET fusion mutations have fewer common mutations, mainly mutations with MDM2, FRS2 and MYC.NRG1 shows a relatively balanced coexistence, especially related to EGFR and CDKN2B.
Research conclusions
This study revealed a comprehensive genetic analysis of the fusion mutation in the sample of NSCLC patients, revealingThe significant differences between different fusion mutations in the load of mutation and common syndrome.In particular, the high TMB of FGFR1-3 fusion mutation indicates that it may be more sensitive to immunotherapy, and the low-TMB NRG1 fusion may show a lower immune response.The covaruing of different types of fusion mutations also provides clues for its potential treatment response, especially the existence of common mutations such as TP53, EGFR, and Pik3ca may affect patients response to targeted therapy and immunotherapy.
The research results show that the mutations characteristics of different fusion mutations in NSCLC are different from the common syndrome, which provides a new perspective for formulating personalized therapy strategies.First of all, FGFR1-3 fusion mutations show a higher TMB, suggesting that they may have a better response to the immune checkpoint inhibitor therapy (such as PD-1/PD-L1 inhibitor)Coordination of other therapies.In addition, the differences in common sudden spectrum further reveal the biological characteristics of different fusion mutations.For example, the low -common mutation rate of ALK and ROS1 fusion mutations and its common mutations with CDKN2A/CDKN2B may explain the good response of these patients to specific targeted therapy.The common mutation features of FGFR1-3, NTRK1-3, and Braf indicate that they have similar mechanisms to EGFR secondary mutations, which may indicate the potential of the combination of EGFR inhibitors and other targeted therapy among these patients.
It is worth noting that the TP53 mutations appear frequently in multiple fusion mutations, especially in the fusion of EGFR, Braf, and FGFR1-3.As an important tumor inhibitory gene, TP53 plays a key role in controlling and maintaining the overallness and stability of the genome.Previous studies have found that the common mutations of TP53 and other driving genes are related to the adverse prognosis of multiple physical tumors [3].In NSCLC, the co-conflict between TP53 and EGFR can cause patients primary or drug-resistant to EGFR-TKI [4].Therefore, for patients with fusion mutations in TP53 common mutations, further research may still be carried out to guide the future more accurate selection of treatment solutions.
In response to the impact of fusion mutations on NSCLC treatment, the NSCLC fusion gene test clinical practice Chinese expert consensus (2023 version) provides important guidance.The consensus is based on the availability of targeted drugs and divides the fusion genes into two types: compulsory genes and expansion genes.The compulsory test gene includes Alk, ROS1, RET, and NTRK; the expansion genes mainly include NRG, FGFR, MET, EGFR, HER2, and Braf, etc. [5].The types of fusion genes involved in this study coincide with the classification of consensus, and the clinical treatment of TMB -related data that is more integrated with genetic mutations provides new perspective and ideas.In the future, in -depth research on fusion mutations and its coexistence spectrum will help further optimize the targeted therapeutic strategies of NSCLC.
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References:
[1] Kazdal D, HOFMAN V, Christopoulos P, et al. Fusion-POSITIVE NON-SMALL LUNG CarCinoma: Biology e, and diagnostic implications [j]. Genes chromosomes car.2022 May; 61 (5): 244-260.
[2] Dongge, L. Et Al. Optimising Targeted Therapy in NSCLC: A Comprehensive Analysis of Oncogenic Fusion M Utations and co-Mutation LandScapes. 2024 ESMO, 1277p.
[3] Le X, Molife C, Leusch Ms, et al. TP53 Co-Mutation With Clinical s in Patients with Egfr-MutantNon-Small Cell Lung Cancer [J]. Cancers (Basel). 2022 DEC 12; 14 (24): 6127.
[4] wang r, pan s, song x.[Research Advances of EGFR-TP53 Co-Mutation in Advanced Non-Small Cell LUNG CANCER] [J].id = "35fovkm4"> [5] The Cancer Pathological Committee of the China Anti-Cancer Association, the Chinese Medical Societys Oncology Branch of the Lung Cancer Expert Committee, the National Pathopathic Quality Control Center.Expert Consensus (2023) [J]. Chinese Pathological Magazine, 2023, 52 (6): 565-573.
Approval Number CN-145980; Expired Date 2025-1-22
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