Circ_0001839 modulates the oncogenic MYCL rs1038259890 (p.G83S) mutation to promote B[a]P-induced malignant...

Benzo[a]pyrene (B[a]P), a major representative of polycyclic aromatic hydrocarbons, has been confirmed by increasing evidence to possess strong mutagenic and carcinogenic properties. Genetic mutations are a central step in tumorigenesis, with driver mutations in oncogenes significantly contributing to cancer development. In this study, we investigated the genetic effects of environmental chemical exposure on carcinogenesis using a well-established malignant transformation model of human bronchial epithelial cells (16HBE-T) induced by chronic exposure to 2.5 μM B[a]P for 90 generations. We found that B[a]P exposure induced gene mutations and altered the expression of circRNAs. Whole-transcriptome sequencing identified that circ_0001839 was consistently downregulated in B[a]P-transformed 16HBE-T cells. Whole-genome sequencing revealed 11 lung cancer-associated driver mutations, including a pathogenic missense mutation in MYCL proto-oncogene (MYCL, rs1038259890, c.247 G>A, p.Gly83Ser) in exon 2, validated by Sanger sequencing confirming a C>T substitution on the template strand. Functional integration analysis demonstrated that circ_0001839 depletion potentiates the oncogenic effects of the MYCL p.Gly83Ser mutation, accelerating B[a]P-induced malignant transformation through dysregulated transcriptional networks. This study explores the regulatory function of circRNAs on gene mutations during chemicals-induced carcinogenesis, offering innovative insights into the toxicological effects and biological pathways of B[a]P on human health.