The NF1 gene mutations and co-mutations in lung adenocarcinomas with brain metastasis
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Date
2025-06
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Publisher
Wolters Kluwer - Medknow
Abstract
Background: The co?occurrence of lung adenocarcinoma and brain metastasisremains a significant cause of morbidity and mortality despite advancements incancer treatment. The activity of neurofibromin, the product of NeurofibromatosisType 1 gene (NF1), is crucial in regulating the RAS/MAPK pathway. TheNF1 somatic mutations are significant in conditions such as melanoma, lungcancer, breast cancer, neuroblastoma, and central nervous system tumors.Objective: Therefore, this research aims to uncover the profile of NF1 mutationsand co-mutations in patients with brain metastases from lung adenocarcinoma,shedding light on their role in the pathophysiology of metastatic lung cancer.Materials and Methods: In this study, a total of 131 (31 females, 90 males)patients diagnosed with metastatic lung adenocarcinoma who were examined inthe Molecular Pathology Laboratory between 2019 and 2022 were retrospectivelyanalyzed. The NF1 somatic mutations and co-mutations were evaluated usingthe NGS lung panel on the MiniSEQ NGS platform. Results: The average ageof the 131 patients (31 females, 90 males) retrospectively examined in thestudy was 62.05 years. The ages of the cases included in the study followeda normal distribution according to Kolmogorov–Smirnov test (P = 0.200).Lymph node metastasis was detected in 48 patients (36.6%), while distantorgan metastasis was observed in 81 patients (61.83%). Metastases weremore frequently seen in males. No statistically significant difference was foundbetween metastases and gender (P > 0.05). Distant organ metastasis (n = 26,19.8%) and NF1 mutations (n = 8/26, 30.77%) were most commonly observedin the brain. The most common NF1 pathogenic variants in brain metastaseswere c.2325 + 3A > G (p.M1205fs*12) (n = 6/26, 23.07%) and c.1400C > T(p.T4671) (n = 5/26, 19.23%). There was no statistically significant relationshipobserved between patients’ age, gender, brain metastasis, and NF1 mutationtypes (respectively, P = 0.98, P = 0.63, and P = 0.87). The mutations that showedthe most association with NF1 mutations in brain metastases were PTEN andTP53. Conclusions: Somatic NF1 mutations and co-mutations can play acritical driving force in metastatic lung adenocarcinoma and may contribute totreatment resistance. The mutational landscape of somatic NF1 mutations andco-mutations can provide new insights into the pathophysiology of metastaticlung cancer, especially those that have metastasized to the brain.
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Keywords
Brain metastasis, comutation, lung adenocarcinoma, neurofibromatosis type 1, NF1 mutations
Citation
Kahraman-Cetin Nesibe, Akin Dilara, Orenay-Boyacioglu Seda, Boyacioglu Olcay, Erdogdu Ibrahim Halil, Oktay Esin, Meteoglu Ibrahim. The NF1 gene mutations and co-mutations in lung adenocarcinomas with brain metastasis. Indian Journal of Pathology & Microbiology. 2025 Jun; 68(2): 294-299