Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel

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. Title: Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel Authors: Ashley M. Brooks, Andrea Vornoli, et al. (including Fiorella Belpoggi from Ramazzini Institute) Journal: PLoS One Publication Date: January 17, 2024 Open-Access Full Text (free PDF/HTML): pmc.ncbi.nlm.nih.gov DOI: 10.1371/journal.pone.0296699 PubMed: pubmed.ncbi.nlm.nih.gov Short Blurb on Why It Matters This paper took archival tumor samples directly from the Ramazzini Institute’s 2018 far-field RF study (the one that found statistically significant increases in heart schwannomas in male rats at very low exposures) and performed detailed histological + immunohistochemical + genetic profiling. Key finding on morphological similarity: The rat gliomas “histologically resemble low-grade human gliomas” and the gliomas and cardiac schwannomas are described as “morphologically similar to low-grade human gliomas.” The paper explicitly notes that about 25–27% of the mutations found in these RF-exposed rat tumors have direct homologs to known human cancer mutations (COSMIC database), strengthening the translational relevance to human health. It also examined the cardiac schwannomas (the same rare tumor type increased in both Ramazzini and NTP studies) and found they harbor mutations in cancer-related genes (e.g., Setd2, Pik3ca, Nf1). This is the “morphological similarity study” people point to when they say the Ramazzini tumors aren’t just “rat-specific weirdness” — they look and behave like the tumors seen in humans, giving the findings much stronger weight for human risk assessment.

AI evidence extraction

Main findings

In Sprague Dawley rats from a lifetime radiofrequency radiation exposure study, increased incidences of gliomas and cardiac schwannomas had been observed, and this paper molecularly characterized those tumors using a targeted rat NGS panel based on 23 human glioma-related genes. Rat gliomas histologically resembled low-grade human gliomas, lacked mutations homologous to human IDH1 p.R132 or IDH2 p.R172 hotspots, and appeared to share some genetic alterations with IDH1-wildtype human gliomas; rat cardiac schwannomas also harbored mutations in some queried cancer genes.

Outcomes measured

• gliomas
• cardiac schwannomas
• single-nucleotide variants (SNVs)
• small insertions and deletions (indels)
• mutations in glioma-related cancer genes
• comparison with COSMIC/human glioma-related mutations

Limitations

• Animal study
• Frequency and SAR not stated in the abstract
• Sample size not stated in the abstract
• Study focuses on molecular characterization/translational relevance rather than estimating exposure-response effects in this abstract

{
    "study_type": "animal",
    "exposure": {
        "band": "RF",
        "source": "other",
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": "lifetime exposure"
    },
    "population": "Sprague Dawley rats",
    "sample_size": null,
    "outcomes": [
        "gliomas",
        "cardiac schwannomas",
        "single-nucleotide variants (SNVs)",
        "small insertions and deletions (indels)",
        "mutations in glioma-related cancer genes",
        "comparison with COSMIC/human glioma-related mutations"
    ],
    "main_findings": "In Sprague Dawley rats from a lifetime radiofrequency radiation exposure study, increased incidences of gliomas and cardiac schwannomas had been observed, and this paper molecularly characterized those tumors using a targeted rat NGS panel based on 23 human glioma-related genes. Rat gliomas histologically resembled low-grade human gliomas, lacked mutations homologous to human IDH1 p.R132 or IDH2 p.R172 hotspots, and appeared to share some genetic alterations with IDH1-wildtype human gliomas; rat cardiac schwannomas also harbored mutations in some queried cancer genes.",
    "effect_direction": "mixed",
    "limitations": [
        "Animal study",
        "Frequency and SAR not stated in the abstract",
        "Sample size not stated in the abstract",
        "Study focuses on molecular characterization/translational relevance rather than estimating exposure-response effects in this abstract"
    ],
    "evidence_strength": "low",
    "confidence": 0.91000000000000003108624468950438313186168670654296875,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "radiofrequency radiation",
        "RFR",
        "Sprague Dawley rats",
        "glioma",
        "cardiac schwannoma",
        "targeted next-generation sequencing",
        "NGS",
        "IDH1",
        "IDH2",
        "COSMIC",
        "animal bioassay",
        "translational relevance"
    ],
    "suggested_hubs": []
}

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