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. 2025 Aug 1;8(8):e2528850.
doi: 10.1001/jamanetworkopen.2025.28850.

Traumatic Brain Injury and Risk of Malignant Brain Tumors in Civilian Populations

Sandro Marini  1   2 , Amr R Alwakeal  3 , Hunter Mills  4 , Joshua D Bernstock  2   5 , Ahmad Mashlah  1   2 , Muhammad T Hassan  3 , Jakob Gerstl  2   5 , Farid Radmanesh  6 , Gundolf Schenk  4 , Sharat Israni  4 , Rachel Grashow  7   8 , E Antonio Chiocca  2   5 , Cathra Halabi  9   10 , Anthony DiGiorgio  11 , Stephen T Magill  3 , Geoffrey T Manley  10   11 , Saef Izzy  1   2   8 , Ross Zafonte  12   13
Affiliations

Traumatic Brain Injury and Risk of Malignant Brain Tumors in Civilian Populations

Sandro Marini et al. JAMA Netw Open. .

Abstract

Importance: A 2024 US study reported that veterans of the Iraq and Afghanistan wars affected by traumatic brain injury (TBI) had an increased risk of developing brain tumors. However, studies among civilians have shown conflicting results and have not replicated the association between TBI and brain tumor risk.

Objective: To examine whether history of TBI in US adult civilians is associated with a risk of subsequent development of malignant brain tumors.

Design, setting, and participants: This retrospective cohort study used data from a tertiary academic medical center (Mass General Brigham [MGB]) patient data registry encompassing January 1, 2000, to January 1, 2024. Adult patients (aged >18 years) with mild TBI or moderate to severe TBI (exposure group) were compared with an age- and sex-matched group without a history of TBI (control group). The MGB data were compared across the same time span with data from 2 other tertiary academic medical centers (University of California [UC] Health Data Warehouse and Northwestern Medicine).

Exposure: TBI, which was categorized by severity as mild or moderate to severe.

Main outcomes and measures: The primary outcome was development of malignant brain tumor based on International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes in the patient data registry of each cohort. Cox proportional hazards regression analysis was used to determine whether TBI was associated with brain tumor development. The MGB results were then meta-analyzed with the UC Health and Northwestern Medicine data.

Results: The MGB cohort included 151 358 adults: 75 679 control participants (51.8% female; median age, 56 years [IQR, 39-71 years]) and 75 679 civilians with TBI. Of the civilians with TBI (median age, 56 years [IQR, 39-74 years]), 60 735 had mild TBI (54.7% female; median age, 54 years [IQR, 37-73 years]) and 14 944 had moderate to severe TBI (42.1% female; median age, 64 years [IQR, 47-79 years]). The median follow-up duration for the MGB cohort was 7.2 years (IQR, 4.1-10.1 years). Malignant brain tumor prevalence was 0.6% in the moderate to severe TBI group vs 0.4% in the control and mild TBI groups. The moderate to severe TBI group had a higher risk of developing malignant brain tumors (hazard ratio [HR], 1.67 [95% CI, 1.31-2.12]) compared with the mild TBI group (HR, 0.99 [95% CI, 0.83-1.18]). The risk persisted when meta-analyzed with data from the other 2 centers (HR, 1.57 [95% CI, 1.26-1.95]).

Conclusions and relevance: In this cohort study of US adult civilians, a history of moderate to severe TBI was associated with risk of developing malignant brain tumors. This association was confirmed in a meta-analysis with geographically diverse sites across the US. Additional research is needed to clarify the mechanism through which TBI increases the risk of developing brain tumors.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Schenk reported receiving grants from the US Department of Defense during the conduct of the study. Dr Chiocca reported serving as an advisor to Bionaut Labs, Seneca Therapeutics, Calidi Biotherapeutics, and Reignite Therapeutics; holding equity options in Bionaut Laboratories, Seneca Therapeutics, Ternalys Therapeutics, and Reignite Therapeutics; and cofounding and serving on the board of directors of Ternalys Therapeutics outside the submitted work. In addition, Dr Chiocca reported receiving research support from the National Institutes of Health (NIH) and the Alliance for Cancer Gene Therapy. Dr Chiocca also reported being a named inventor on patents related to oncolytic herpes simplex virus 1 and noncoding RNAs, owned by Mass General Brigham who has licensed these to third parties. Dr Halabi reported receiving grants from the Pac-12 Student Health and Wellbeing Initiative, the Weill Institute for Neurosciences Neurohub, the University of California Noyce Initiative, and the National Institute on Deafness and Other Communication Disorders outside the submitted work. Dr DiGiorgio reported receiving grants from DePuy Synthes, the Charles Koch Foundation, and the Florida Essential Healthcare Partnership outside the submitted work. Dr Manley reported receiving specimen collection support from Abbott Laboratories and grants from the National Football League (NFL) Scientific Advisory Board Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Longitudinal study outside the submitted work. Dr Zafonte reported serving on the scientific advisory boards of Myomo and NanoDx and as a member of the Mackey White Committee of the NFL Players Association outside the submitted work. In addition, Dr Zafonte reported receiving funding from the National Institute on Disability, Independent Living, and Rehabilitation Research, the NIH, and the Football Players Health Study at Harvard University. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart of the Mass General Brigham (MGB) Cohort
TBI indicates traumatic brain injury.
Figure 2.
Figure 2.. Kaplan-Meier Curves for Malignant Brain Tumor Incidence Across Patients With Traumatic Brain Injury (TBI) and Control Participants in the Mass General Brigham Cohort
The y-axis is restricted to 97% to 100% for visibility. Shaded areas indicate 95% CIs.
Figure 3.
Figure 3.. Forest Plot of the Random-Effects Model With Inverse Variance Method Meta-Analysis of Malignant Brain Tumor Risk Among Participants With Moderate to Severe Traumatic Brain Injury (TBI) Across 3 Cohorts
The different box sizes reflect the weight of each study in the meta-analysis. HR indicates hazard ratio; MGB, Mass General Brigham; UC, University of California.
See this image and copyright information in PMC

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