Analysis of a pan-cancer panel reveals the amino acid metabolism-related gene MTHFD1 as a potential prognostic and immunotherapeutic biomarker

Our plain-English summary of Analysis of a pan-cancer panel reveals the amino acid metabolism-related gene MTHFD1 as a potential prognostic and immunotherapeutic biomarker, by S. Gong, J. Yang, C. Pan, et al (Experimental and Therapeutic Medicine, 2025).

The study

• Authors: S. Gong, J. Yang, C. Pan, F. Peng, C. Pan
• Journal: Experimental and Therapeutic Medicine
• Published: 2025;30(1):142
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) serves a role in amino acid metabolism and may influence tumor progression. However, to the best of our knowledge, a comprehensive analysis of MTHFD1 in various types of cancer has not been previously performed. Therefore, the present study aimed to investigate the expression profile and prognostic implication of MTHFD1 across various types of cancer, whilst assessing its potential as a novel biomarker and therapeutic target. The expression of MTHFD1 in tissues from various types of cancer was analyzed using online tools based on data from the Cancer Cell Line Encyclopedia and Clinical Proteomic Tumor Analysis Consortium, as well as in-house differential expression analysis using data from The Cancer Genome Atlas (TCGA). The association between MTHFD1 and prognosis was investigated using Kaplan-Meier survival analysis and Cox proportional hazards regression analysis based on TCGA datasets. Furthermore, the association between MTHFD1 and the tumor microenvironment (TME) was investigated using the 'estimation of stromal and immune cells in malignant tumor tissues using expression data' and 'cell-type identification by estimating relative subsets of RNA transcripts' algorithms. The correlation between MTHFD1 expression and tumor mutational burden (TMB), microsatellite instability (MSI) or 48 immune checkpoint blockade-related gene expression levels was investigated using Pearson correlation analyses. The predictive potential of MTHFD1 for immunotherapy efficacy was evaluated using the tumor immune dysfunction and exclusion (TIDE) algorithm with the IMvigor210 dataset. Subsequently, the effects of MTHFD1 on the proliferation and invasion of A549 and 786-O cell lines were assessed using colony formation and Transwell assays. Analysis across 33 tumor types revealed that MTHFD1 expression was significantly upregulated in 12 cancers (e.g., bladder urothelial carcinoma) and downregulated in 6 cancers (e.g., breast invasive carcinoma). Moreover, high MTHFD1 expression was associated with a poorer prognosis in kidney chromophobe and lung adenocarcinoma, but with better prognosis in kidney renal clear cell carcinoma. Additionally, the activity of MTHFD1, evaluated using the single-sample Gene Set Enrichment Analysis algorithm, was significantly upregulated in 21 cancer types, including bladder urothelial carcinoma and breast invasive carcinoma, compared with corresponding normal tissues. MTHFD1expression levels were negatively correlated with immune cell infiltration in 16 tumor types [e.g., adrenocortical carcinoma (ACC)] and positively correlated only in uveal melanoma (UVM). Additionally, MTHFD1 expression levels showed significant correlations with TMB in 17 tumors (e.g., ACC), were negatively correlated with TIDE scores in most tumors except mesothelioma, liver hepatocellular carcinoma, diffuse large B-cell lymphoma and cholangiocarcinoma, and were associated with MSI in 9 tumor types (e.g., UVM). Multivariant Cox regression analysis revealed that MTHFD1 expression was an independent risk factor for prognosis in lung adenocarcinoma, whilst it was an independent protective factor in clear cell renal cell carcinoma, highlighting its distinct prognostic roles in these two tumor types. In vitro experiments found that knocking down or overexpressing MTHFD1 in A549 and 786-O cells, respectively, reduced the corresponding malignant phenotypes. Overall, to the best of our knowledge, results of the present study provided the first comprehensive analysis of MTHFD1 as a potential cancer biomarker and highlighted its role in immune suppression within the TME. These findings suggested that targeting MTHFD1 may be a novel therapeutic strategy, which may enhance the efficacy of immunotherapy and improve the outcomes of patients with various types of cancer.

Copyright: © 2025 Gong et al.

In plain English

This was a laboratory and computer-based study of a gene called MTHFD1 across 33 cancer types. It was not a study of asbestos. The authors analyzed public gene-expression, survival and mutation data, mainly from The Cancer Genome Atlas (TCGA), and ran cell experiments on one lung adenocarcinoma cell line (A549) and one kidney clear cell carcinoma cell line (786-O). Mesothelioma was one of the 33 tumor types. In mesothelioma, MTHFD1 was flagged as a prognostic factor for overall survival and was associated with progression-free survival. Mesothelioma was also one of four tumor types where MTHFD1 showed no correlation with an immunotherapy-response score called TIDE. The article does not say how many mesothelioma cases were analyzed and does not describe any asbestos exposure. Across cancers, high MTHFD1 was linked to worse outcomes in some types and better outcomes in others. The authors concluded that MTHFD1 may play a cancer-promoting role in lung adenocarcinoma and a suppressing role in kidney clear cell carcinoma in cell experiments. They noted that their work used public databases and lacked primary patient data.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics analysis of public cancer databases (TCGA, GTEx, CCLE, CPTAC, IMvigor210) combined with in vitro cell-line experiments
• Who was studied: Public database tumor and normal tissue data for 33 tumor types, including mesothelioma (patient numbers not reported); the IMvigor210 dataset of patients with metastatic urothelial carcinoma treated with atezolizumab; and two cell lines (A549 lung adenocarcinoma, 786-O kidney clear cell carcinoma)
• Exposure: No asbestos or other environmental or occupational exposure was studied. The factor examined was expression of the MTHFD1 gene, including knockdown and overexpression in cell lines.
• Main results:
  • MTHFD1 expression differed significantly between tumor and normal tissue in 18 of the 33 tumor types
  • In univariate Cox regression, MTHFD1 was a prognostic factor for overall survival in several tumor types including mesothelioma (direction for mesothelioma not stated in the text)
  • MTHFD1 expression was associated with progression-free survival in ten tumor types, including mesothelioma
  • In Kaplan-Meier analysis, low MTHFD1 expression was linked to longer overall survival in six tumor types. Mesothelioma was not among them.
  • MTHFD1 expression was negatively correlated with immune cell infiltration in 16 of 33 tumor types
  • MTHFD1 showed no correlation with TIDE scores in mesothelioma and three other tumor types
  • In mesothelioma, MTHFD1 expression was negatively correlated with the immune checkpoint gene CD274
  • In the IMvigor210 dataset, MTHFD1 expression was higher in patients who responded to immune checkpoint inhibitors than in non-responders
  • In multivariate Cox analysis, MTHFD1 expression was an independent risk factor in lung adenocarcinoma and an independent protective factor in kidney clear cell carcinoma
  • Overexpressing MTHFD1 in the kidney clear cell carcinoma cell line reduced cell proliferation and migration. Knocking it down in the lung adenocarcinoma cell line also inhibited proliferation and migration.
• The authors' conclusion: The authors concluded that MTHFD1 may have an oncogenic role in lung adenocarcinoma and a tumor-suppressive role in kidney clear cell carcinoma in vitro, and may serve as a predictive marker for immunotherapy response
• Limitations the authors state:
  • Relied on public databases without primary patient data
  • No single-cell sequencing data
  • No immune cell infiltration experiments in animals or clinical specimens
  • Cell experiments covered only two cancer types
  • Mechanisms of immunotherapy efficacy were not investigated

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Prognosis, Tumor Microenvironment, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI-H), Immunotherapy, Carcinoma, Lung Adenocarcinoma.

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