Abstract
Background
Glioma is the most common malignant primary brain tumor and is associated with significant morbidity and mortality. Modifiable risk factors remain unidentified. New advances in exposure assessment, genomic analyses, and statistical techniques permit more accurate evaluation of glioma risk associated with exogenous occupational or environmental exposures.
Methods
By using whole‐exome sequencing data from matched germline and glioma tumor samples, the authors compared tumor mutational signatures for 17 persons with glioma and a documented occupational history of firefighting with those of 18 persons with glioma without an occupational history of firefighting. All 35 individuals were participants in the University of California, San Francisco Adult Glioma Study.
Results
There was a positive correlation among firefighters between the median number of sample variants attributable to single‐base substitution signature 42, a single‐base substitution mutational signature associated with haloalkane exposure (from the Catalogue of Somatic Mutational Signatures in Cancer) and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to single‐base substitution signature 42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic.
Conclusions
In summary, the authors identified gliomas that had mutational signatures associated with haloalkane exposure that were enriched in firefighters and other occupations.
Keywords: epidemiology, firefighters, glioma, haloalkane, mutation, occupation, signature
Short abstract
By using whole‐exome sequencing data from matched germline and tumor samples, the authors identify gliomas that had mutational signatures associated with haloalkane exposure and were enriched in firefighters and other occupations in the University of California, San Francisco Adult Glioma Study.
INTRODUCTION
Gliomas are associated with significant morbidity and mortality, motivating attempts to discover risk factors through large‐scale epidemiology, genetic, and neuropathology collaborations. 1 , 2 , 3 , 4 , 5 , 6 To date, with the exception of ionizing radiation 7 and possibly air pollution, 8 , 9 results are inconsistent for environmental factors, and most identified genetic variants conferring significant risk are rare. 7
We recently identified specific mutational signatures matched to those reported in the Catalogue of Somatic Mutational Signatures in Cancer (COSMIC; Wellcome Sanger Institute) using 1000 gliomas available from The Cancer Genome Atlas (TCGA) and Glioma Longitudinal Analysis (GLASS). 1 Although most glioma mutation signatures were related to the aging process single‐base substitution signature 1 (SBS1), signatures from environmental haloalkane exposures were present in some gliomas, particularly in men. This mutational signature (single‐base substitution signature 42; SBS42) was first identified in association with occupational cholangiocarcinoma among the workers from a printing company in Japan. 10 Haloalkanes are widely used commercially (as well as in the home) in flame retardants, fire extinguishants, and pesticides and are an intriguing finding given the observed increased glioma risk noted in firefighters from the Adult Glioma Study (AGS). 5 Recently, in one of the first efforts to directly assess chemical exposure and glioma cell toxicity, researchers treated oligodendrocyte progenitor cells with a panel of almost 2000 chemicals and observed that organophosphate flame retardants prematurely arrested oligodendrocyte maturation, lending further support to the role of this exposure in gliomagenesis. 11
MATERIALS AND METHODS
Because no data on occupational or environmental exposure histories were available for the TCGA/GLASS patient samples used in our prior analysis 1 and to validate our findings in a separate group of patients, we now compare mutational signatures for 17 individuals with glioma and a documented occupational history of firefighting versus those of 18 individuals who had glioma without an occupational history of firefighting. Individuals with glioma were drawn from the case–control University of California, San Francisco (UCSF) Adult Glioma Study (AGS), between 1991 and 2013. 5 The AGS included greater than 3000 adults aged 18 years and older who had a newly diagnosed glioma between 1991 and 1994 (series 1), 1997 and 1999 (series 2), 2001 and 2004 (series 3), 2006 and 2010 (series 4), and 2010 and 2013 (series 5). Population‐based individuals with glioma (series 1–4) resided in the San Francisco Bay Area, and clinic‐based patients (series 3–5) were recruited to participate while seeking care at the UCSF Neuro‐Oncology Clinic, regardless of their place of residence. Participants were interviewed about various factors, including occupational history and treatment, and provided blood specimens at the time of the interview for research purposes. Pathology was centrally reviewed by a UCSF neuropathologist during the original recruitment period, and tumor specimens were obtained from consenting patients. Various tumor marker assays, including IDH mutation and 1p/19q co‐deletion, were later conducted; World Health Organization 2016 diagnoses were later assigned to most of these patients. 3 , 12 From this patient cohort, we identified 17 firefighters with glioma for whom blood and tumor samples were available. Individuals with glioma (n = 18) who reported no occupational history of firefighting were matched to the firefighter group on age, sex, blood collection year, race, dexamethasone use, chemotherapy and radiation exposure before the collection of blood, days since chemotherapy, days since radiation, and glioma subtype. 6 Paired blood and treatment‐naive tumor DNA samples from each patient were prepared at UCSF and sent to the Yale Center for Genomic Analysis for whole‐exome sequencing. 13 Next‐generation sequencing libraries were prepared from 100 ng each of paired normal whole‐blood and formalin‐fixed, paraffin‐embedded tumor‐derived DNA using the IDT xGen formalin‐fixed, paraffin‐embedded DNA library Prep Kit (Integrated DNA Technologies, Inc.). Paired‐end, 100‐base‐pair sequencing was performed on the NovaSeq S4 platform to a depth of 50x for normal libraries and 100x for tumor‐derived libraries (Illumina, Inc.).
Molecular data were prepared and analyzed with the cancereffectsizeR package, 14 which uses the MutationalPatterns package 15 for signature refitting and reports the number of substitutions within a sample attributable to each detectable signature. Data were filtered in accordance with the steps outlined by Cannataro et al. in 2022, 16 wherein all variants in >0.04% of any gnomAD subpopulation were dropped, along with variants not at a statistically different variant allele frequency with the paired normal sample (Boschloo exact test; dropped if p > .05). Variants within one or two base pairs of one another were also dropped because these variants are likely not independent (e.g., double‐base substitutions). COSMIC signatures previously identified within glioblastoma multiforme (GBM) 17 were refit to all nonrecurrent single nucleotide variants within our data set. 18 Signatures were refitted 1000 times per sample using the bootstrapping functionality of MutationalPatterns. To highlight probable driver genes within our data that have a high likelihood of being attributable to the COSMIC SBS42 signature, GBM data from GLASS 19 and TCGA 20 were combined with our data and the dndscv package, 21 informed with GBM‐specific covariates of mutation rate, 22 and used to detect genes with significantly more variants than expected under assumptions of neutrality. The probability that the SBS42 signature contributed to each variant, given the variant's trinucleotide context and the mutational weights within the tumor calculated in each bootstrap resampling, were calculated using cancereffectsizeR. 18
RESULTS
The 17 firefighters and 18 nonfirefighters with glioma were primarily men (94%) who reported being White and of non‐Hispanic ethnicity (Table 1). They worked as firefighters for an average of 22 years and were diagnosed approximately 7 years after the last reported firefighter exposure, on average. Most tumors were IDH1/IDH2 wild type and of high grade (glioblastoma). Most participants received chemotherapy (temozolomide) and radiation prior to blood collection.
TABLE 1.
Characteristics of University of California, San Franciso Adult Glioma Study participants diagnosed from 1991 to 2013 included in this report.
| Characteristic | Firefighters with glioma, n = 17 | Nonfirefighters with glioma, n = 18 a | p | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Age at diagnosis, years | |||||
| 30–39 | 1 | 5.9 | 1 | 5.6 | |
| 40–49 | 3 | 17.6 | 3 | 16.7 | |
| 50–59 | 4 | 23.5 | 8 | 44.4 | |
| 60–69 | 8 | 47.1 | 4 | 22.2 | |
| ≥70 | 1 | 5.9 | 2 | 11.1 | |
| Age: Average ± SD, years | 56.3 ± 8.8 | 55.9 ± 9.6 | .90 | ||
| Sex | |||||
| Male | 16 | 94.1 | 17 | 94.4 | 1.00 |
| Female | 1 | 5.9 | 1 | 5.6 | |
| Race | |||||
| White | 17 | 100.0 | 18 | 100.0 | 1.00 |
| Non‐White | 0 | 0.0 | 0 | 0.0 | |
| Ethnicity | |||||
| Hispanic | 1 | 5.9 | 0 | 0.0 | .49 |
| Non‐Hispanic | 16 | 94.1 | 18 | 100.0 | |
| Firefighting exposure, total years | |||||
| 1–9 | 3 | 17.7 | NA | — | |
| 10–19 | 2 | 11.8 | NA | — | |
| 20–29 | 8 | 47.1 | NA | — | |
| 30–39 | 4 | 23.5 | NA | — | |
| Average ± SD | 22.2 ± 10.0 | ||||
| Time from last firefighting exposure to diagnosis, years | |||||
| 0‐4 | 9 | 52.9 | NA | — | |
| 5‐9 | 3 | 17.6 | NA | — | |
| 10‐19 | 1 | 5.9 | NA | — | |
| 20‐29 | 1 | 5.9 | NA | — | |
| 30‐39 | 1 | 5.9 | NA | — | |
| Unknown | 2 | 11.8 | NA | — | |
| Average ± SD | 7.3 ± 10.9 | — | — | ||
| Histologic diagnosis | |||||
| Glioblastoma | 12 | 70.6 | 12 | 66.7 | .79 |
| Astrocytoma, grade 3 | 1 | 5.9 | 1 | 5.6 | |
| Astrocytoma, grade 2 | 2 | 11.8 | 2 | 11.1 | |
| Oligodendroglioma, grade 3 | 1 | 5.9 | 0 | 0.0 | |
| Oligodendroglioma, grade 2 | 0 | 0.0 | 2 | 11.1 | |
| Oligoastrocytoma, grade 2 | 0 | 0.0 | 1 | 5.6 | |
| Other | 1 | 5.9 | 0 | 0.0 | |
| IDH1 mutation | |||||
| Wild type | 14 | 82.4 | 14 | 77.8 | 1.00 |
| Mutated | 3 | 17.7 | 4 | 22.2 | |
| 1p/19q status b | |||||
| Not co‐deleted | 13 | 76.5 | 15 | 83.3 | .00 |
| Co‐deleted | 2 | 11.8 | 3 | 16.7 | |
| Unknown | 2 | 11.8 | 0 | 0.0 | |
| Median | IQR (min/max) | Median | IQR (min/max) | |
|---|---|---|---|---|
| Tumor mutational burden, mutations/Mb | 56.0 | 11.0 (26.0/69.0) | 55.5 | 31.75 (25.0/102.0) |
| Mean contribution to mutation burden of SBS1 c | 0.369 | 0.382 |
Abbreviations: IQR, interquartile range; max, maximum; min, minimum; NA, not applicable.; SBS1, single‐base substitution signature 1 (glioma mutation signatures related to the aging process); SD, standard deviation.
Two nonfirefighters with glioma were matched to the firefighter who had a noted IDH mutation but had unknown 1p/19q status. For this patient, we selected both a nonfirefighter with a low‐grade IDH‐mutant astrocytoma and another with an IDH‐mutant oligodendroglioma.
Some of these patients were classified as not co‐deleted based on our Adult Glioma Study 1p/19q imputation algorithm. 3
Values indicate the clock‐like Catalogue of Somatic Mutational Signatures mutational signature mean value among samples of the median SBS1 signature contribution after bootstrapping.
Thirteen of the 35 samples had a median number of variants attributable to SBS42 greater than zero (Figure 1). Among firefighters, there were two individuals with a high median number of variants attributable to SBS42 and a low number of firefighting years; however, these individuals had additional self‐described occupations that possibly exposed them to haloalkanes, such as farming, pesticide use, and petroleum transport 23 (Figure 1A). Removing these two individuals, there was a positive correlation among firefighters between the median number of variants in the samples attributable to SBS42 and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to SBS42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic (Figure 1A).
FIGURE 1.
The median number of mutations attributable to SBS42 among 1000 bootstrap resamplings of variant data, with (A) occupations and (B) variants highlighted. (A) Points correspond to firefighters with a nonzero median SBS42 attribution who had <10 firefighting years and nonfirefighters who had the two greatest median attributable SBS42 mutations and had self‐reported occupation. (B) Variants considered significantly mutated are highlighted (Q < 0.1; green text, with median probability [across 1000 bootstrap samplings] that each variant is attributable to SBS42). In addition, four tumors with >10 median attributable SBS42 variants but without a variant considered significantly mutated have a COSMIC tier 1‐curated variant highlighted, (orange text, with the median probability [across 1000 bootstrap samplings] that each variant is attributable to SBS42). COSMIC indicates the Catalogue of Somatic Mutational Signatures in Cancer; SBS42, single‐base substitution signature 42.
The SBS42 signature is the likely source of many variants within several samples and also is the most likely source of specific variants that are possible drivers of the cancer phenotype within these samples (Figure 1B). Among the 13 samples with a median SBS42 variant attribution greater than zero, six had at least one significantly mutated gene, of which five had a >50% median likelihood of SBS42 being the signature driving the variant. In addition, samples with >10 median variants attributable to SBS42 also contain variants in NOTCH1, ROS1, ETV1, and NCOA2—genes curated within the COSMIC tier 1 list of genes with documented activity relevant to cancer—with a >60% median likelihood of being attributable to SBS42.
CONCLUSIONS
Glioma is largely associated with aging and mutational signatures relating to endogenous mutational processes that correlate with age, such as spontaneous or enzymatic deamination of 5‐methylcytosine. However, some gliomas have detectable signatures associated with exogenous mutational processes, such as SBS42 haloalkanes. In these data, we confirm detection of this signature in a cohort of individuals likely highly exposed to haloalkanes, i.e., long‐term firefighters. Identifying exogenous mutational processes in cancers is extremely important because they may inform public health intervention strategies to reduce mutagenesis and prevent cancer inception. Identifying occupational correlates with SBS42, associated with occupational exposure to haloalkanes, will pinpoint occupational hazards that may be avoidable. This is especially important for cancers in which exogenous mutagenesis is not well established.
AUTHOR CONTRIBUTIONS
Vincent L. Cannataro: Software; formal analysis; data curation; writing—review and editing; methodology. Paige M. Bracci: Funding acquisition; writing—review and editing. Jennie W. Taylor: Funding acquisition; writing—review and editing. Lucie McCoy: Project administration; data curation; writing—review and editing. Terri Rice: Project administration; data curation; writing—review and editing. Helen M. Hansen: Data curation; project administration. Anne E. Heffernan: Formal analysis; writing—review and editing. Joseph Wiemels: Writing—review and editing. John Wiencke: Funding acquisition. Margaret Wrensch: Funding acquisition; writing—review and editing; project administration; supervision; resources. Elizabeth B. Claus: Conceptualization; investigation; funding acquisition; writing—original draft; project administration; supervision; resources; methodology.
CONFLICT OF INTEREST STATEMENT
Paige M. Bracci reports stock ownership in Neuvivo Inc. outside the submitted work. C ‐advisory board Servier Pharmaceuticals Jennie W. Taylor reports grant funding from Servier Pharmaceuticals and Bristol‐Meyers Squibb; advisory board fees from Servier Pharmaceuticals; consulting fees from Mount Sinai Health Systems and the University of Colorado; and royalties from UpToDate outside the submitted work. Elizabeth B. Claus reports advisory board fees from Servier Pharmaceuticals outside the submitted work. John Wiencke is cofounder of Cellintec, which played no role in the current work. The remaining authors disclosed no conflicts of interest.
ACKNOWLEDGMENTS
This work was supported by the National Cancer Institute (Grant 5U2C‐CA252979) to Elizabeth B. Claus. Sequencing and analysis of the samples were performed by the Yale Center for Genome Analysis, which is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 1S10OD030363‐01A1.
Work at University of California, San Francisco (UCSF) was also supported by additional grants from the National Institutes of Health (Grants R01CA52689, P50CA097257, R01CA126831, R01CA139020, and R25CA112355), the Loglio Collective, the National Brain Tumor Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, the Robert Magnin Newman Endowed Chair in Neuro‐oncology, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, and William Martinusen.
We acknowledge the support of the UCSF Academic Senate Committee on Research. Support for this research was provided by Core Center Grant P30‐ES030284 from the National Institute of Environmental Health Sciences, National Institutes of Health. This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through the UCSF Clinical and Translational Science Institute (Grant UL1 RR024131). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; the Centers for Disease Control and Prevention's National Program of Cancer Registries under Cooperative Agreement 5NU58DP006344; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under Contract HHSN261201800032I awarded to the UCSF; Contract HHSN261201800015I awarded to the University of Southern California; and Contract HHSN261201800009I awarded to the Public Health Institute, Cancer Registry of Greater California. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, the Department of Public Health, the National Cancer Institute, or the Centers for Disease Control and Prevention or their contractors and subcontractors.
We acknowledge the study participants, the clinicians and research staff at the participating medical centers; the UCSF Helen Diller Family Comprehensive Cancer Center Genome Analysis Core, which is supported by a National Cancer Institute Cancer Center Support Grant (5P30CA082103); the UCSF Cancer Registry; and the UCSF Neurosurgery Tissue Bank. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the National Cancer Institute and the National Human Genome Research Institute. Information about The Cancer Genome Atlas can be found at http://cancergenome.nih.gov.
Cannataro VL, Bracci PM, Taylor JW, et al. Glioma mutational signatures associated with haloalkane exposure are enriched in firefighters. Cancer. 2025;e35732. doi: 10.1002/cncr.35732
DATA AVAILABILITY STATEMENT
Code is available at https://github.com/Cannataro‐Lab/glioma_FF_haloalkane. The data that support the findings of this study are available upon reasonable request from the University of California, San Francisco authors at [email protected] or [email protected]. The data are not publicly available because of privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Code is available at https://github.com/Cannataro‐Lab/glioma_FF_haloalkane. The data that support the findings of this study are available upon reasonable request from the University of California, San Francisco authors at [email protected] or [email protected]. The data are not publicly available because of privacy or ethical restrictions.