Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation

Abstract

Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel Brooks AM, Vornoli A, Kovi RC, Ton TVT, Xu M, Mashal A, Tibaldi E, Gnudi F, Li JL, Sills RC, Bucher JR, Mandrioli D, Belpoggi F, Pandiri AR. Genetic profiling of rat gliomas and cardiac schwannomas from life- time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel. PLoS One. 2024 Jan 17;19(1):e0296699. doi: 10.1371/journal.pone.0296699. Abstract The cancer hazard associated with lifetime exposure to radiofrequency radiation (RFR) was examined in Sprague Dawley (SD) rats at the Ramazzini Institute (RI), Italy. There were increased incidences of gliomas and cardiac schwannomas. The translational relevance of these rare rat tumors for human disease is poorly understood. We examined the genetic alterations in RFR-derived rat tumors through molecular characterization of important cancer genes relevant for human gliomagenesis. A targeted next-generation sequencing (NGS) panel was designed for rats based on the top 23 orthologous human glioma-related genes. Single-nucleotide variants (SNVs) and small insertion and deletions (indels) were characterized in the rat gliomas and cardiac schwannomas. Translational relevance of these genetic alterations in rat tumors to human disease was determined through comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) database. These data suggest that rat gliomas resulting from life- time exposure to RFR histologically resemble low grade human gliomas but surprisingly no mutations were detected in rat gliomas that had homology to the human IDH1 p.R132 or IDH2 p.R172 suggesting that rat gliomas are primarily wild-type for IDH hotspot mutations implicated in human gliomas. The rat gliomas appear to share some genetic alterations with IDH1 wildtype human gliomas and rat cardiac schwannomas also harbor mutations in some of the queried cancer genes. These data demonstrate that targeted NGS panels based on tumor specific orthologous human cancer driver genes are an important tool to examine the translational relevance of rodent tumors resulting from chronic/life-time rodent bioassays. Excerpts In this study we have demonstrated that the gliomas and cardiac schwannomas in rats resulting from lifetime exposure to low dose far field RFR that are used for cellular telephone communications, are morphologically similar to low grade human gliomas and that about 25% of the mutations seen in these tumors have corresponding alterations in homologs of human cancer genes. Surprisingly, none of the rat gliomas examined in this study harbored mutations in Idh1/2 genes that are common in human gliomas.... In summary, our results demonstrate that regardless of their etiology (due to lifetime RFR exposure or arising spontaneously), rat gliomas are primarily Idh1/2 wild type unlike most human gliomas. Histologically, most of the rat gliomas resemble diffuse low-grade gliomas in humans and such gliomas that do not harbor IDH1/2 mutations in humans are known to have poor prognosis. The genetic alterations in other cancer genes evaluated in this panel provide novel insights into tumor progression in rat gliomas and cardiac schwannomas. The relevance of specific mutations to human cancers is variable, with some genes (Tp53, Cdkn2a, Erbb2, Chek2, Kras and Pik3r1) harboring many alterations with COSMIC relevance while the opposite is true for other target genes (Idh1/2, Atrx, Notch1, Pten, Rb1 and Setd2). Several of these conserved mutations in rat tumors do not have comparable alterations in the COSMIC database, suggesting that the orthologous mutations could have different functional consequences in rat carcinogenesis and deserve further study. An important consideration is that molecular differences underlying mutational processes contribute to distinct mutational patterns which could be the result of similar etiology, albeit by different mechanisms. Several of the variants that were detected in gliomas were also observed in non-tumor brain tissues from interim time point providing an insight into the molecular pathogenesis in rodent carcinogenicity studies and these strategies may be utilized to potentially estimate the cancer hazard risk in shorter term animal studies. Finally, this targeted mutation panel may be refined using data from whole genome or exome sequencing of rat tumors and performing error corrected duplex sequencing to increase the sensitivity to detect rare mutations in exposed non-tumor tissues from early time points. Open access paper: journals.plos.org

AI evidence extraction

Main findings

The paper reports that in the underlying lifetime RFR exposure study in Sprague Dawley rats there were increased incidences of gliomas and cardiac schwannomas. Targeted NGS of 23 orthologous human glioma-related genes found that rat gliomas from lifetime RFR exposure histologically resembled low-grade human gliomas but did not show mutations homologous to human IDH1 p.R132 or IDH2 p.R172, suggesting the rat gliomas were primarily IDH1/2 wild-type; some mutations overlapped with alterations reported in COSMIC and cardiac schwannomas also harbored mutations in queried cancer genes.

Outcomes measured

• Gliomas incidence (reported as increased in the underlying lifetime RFR bioassay)
• Cardiac schwannomas incidence (reported as increased in the underlying lifetime RFR bioassay)
• Tumor genetic alterations (SNVs and small indels) in 23 glioma-related genes
• Presence/absence of IDH1/IDH2 hotspot mutations (IDH1 p.R132; IDH2 p.R172 homologs)
• Comparability of rat tumor mutations to human cancer mutations (COSMIC)
• Histologic resemblance of rat gliomas to low-grade human gliomas

Limitations

• Frequency and SAR/exposure metrics not provided in the abstract
• Sample size and number of tumors sequenced not stated in the abstract
• Genetic profiling used a targeted 23-gene panel (may miss other relevant alterations)
• Translational relevance to human disease is described as poorly understood/variable

Suggested hubs

• who-icnirp (0.22)
  Animal evidence on cancer outcomes from lifetime RF exposure is relevant to RF health-risk evaluation frameworks.

{
    "study_type": "animal",
    "exposure": {
        "band": "RF",
        "source": "cellular telephone communications (far field)",
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": "lifetime/chronic"
    },
    "population": "Sprague Dawley rats (Ramazzini Institute, Italy)",
    "sample_size": null,
    "outcomes": [
        "Gliomas incidence (reported as increased in the underlying lifetime RFR bioassay)",
        "Cardiac schwannomas incidence (reported as increased in the underlying lifetime RFR bioassay)",
        "Tumor genetic alterations (SNVs and small indels) in 23 glioma-related genes",
        "Presence/absence of IDH1/IDH2 hotspot mutations (IDH1 p.R132; IDH2 p.R172 homologs)",
        "Comparability of rat tumor mutations to human cancer mutations (COSMIC)",
        "Histologic resemblance of rat gliomas to low-grade human gliomas"
    ],
    "main_findings": "The paper reports that in the underlying lifetime RFR exposure study in Sprague Dawley rats there were increased incidences of gliomas and cardiac schwannomas. Targeted NGS of 23 orthologous human glioma-related genes found that rat gliomas from lifetime RFR exposure histologically resembled low-grade human gliomas but did not show mutations homologous to human IDH1 p.R132 or IDH2 p.R172, suggesting the rat gliomas were primarily IDH1/2 wild-type; some mutations overlapped with alterations reported in COSMIC and cardiac schwannomas also harbored mutations in queried cancer genes.",
    "effect_direction": "harm",
    "limitations": [
        "Frequency and SAR/exposure metrics not provided in the abstract",
        "Sample size and number of tumors sequenced not stated in the abstract",
        "Genetic profiling used a targeted 23-gene panel (may miss other relevant alterations)",
        "Translational relevance to human disease is described as poorly understood/variable"
    ],
    "evidence_strength": "low",
    "confidence": 0.7399999999999999911182158029987476766109466552734375,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "radiofrequency radiation",
        "RFR",
        "Sprague Dawley rats",
        "Ramazzini Institute",
        "glioma",
        "cardiac schwannoma",
        "targeted next-generation sequencing",
        "SNV",
        "indel",
        "IDH1",
        "IDH2",
        "COSMIC",
        "translational relevance",
        "rodent bioassay"
    ],
    "suggested_hubs": [
        {
            "slug": "who-icnirp",
            "weight": 0.2200000000000000011102230246251565404236316680908203125,
            "reason": "Animal evidence on cancer outcomes from lifetime RF exposure is relevant to RF health-risk evaluation frameworks."
        }
    ]
}

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