LAM is a rare progressive lung diseases with neoplastic traits, which to date is known to be caused by mutations in the TSC2 gene leading to a hyperactivated mTOR pathway with uncontrolled cell growth. However, other mutations may contribute to disease progression. Here, we investigate the role of potential co-mutations, specifically the FGFR4 p.Gly388Arg polymorphism, previously identified as marker for aggressive cancer progression, as a potential co-driver in LAM. Peripheral blood mononuclear cells (PBMCs) from seven sporadic LAM patients were isolated and analyzed, using Next-Generation Sequencing (NGS) to identify tumorigenic mutations. The FGFR4 p.Gly388Arg variant was identified in four patients, with allelic frequencies ranging from 49% to 99%. The highest frequency was found in a patient with severe bullous lung disease, who eventually required lung transplantation. A moderate correlation (r = 0.55) between FGFR4 allelic frequency and lung function decline (FEV1%) suggests that this mutation may accelerate disease progression. Our findings indicate that FGFR4 mutations may play a role in the systemic nature of LAM, potentially exacerbating disease severity. Further research is required to explore FGFR4 as a biomarker and therapeutic target alongside mTOR inhibitors in LAM treatment strategies.

The authors have declared no competing interest.

This study was supported by the German Research Foundation (DFG) (Grant No. KO5803/2-1 to SKG), the Federal Ministry for Research and Education Germany (BMBF) (Grant No. 01EO2102 to SKG) and departmental funds from the Department of Internal Medicine, Goethe University Frankfurt.

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Written informed consent was obtained from all patients and the study was approved by the Institutional Review Boards of the University Cancer Center (UCT) and the Ethics Committee at the University Hospital Frankfurt (project number: STO-02-2017).

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Funding: This study was supported by the German Research Foundation (DFG) (Grant No. KO5803/2- 1 to SKG), the Federal Ministry for Research and Education Germany (BMBF) (Grant No. 01EO2102 to SKG) and departmental funds from the Department of Internal Medicine, Goethe University Frankfurt.

All data produced in the present study are available upon reasonable request to the authors