Comprehensive Molecular Characterization of Mitochondrial Genomes in Spontaneous and Chemical-induced Hepatocellular Carcinomas in B6C3F1/N mice

Authors

• M Xu
• A Burkholder
• D Fargo
• J Marzec
• S Kleeberger
• G Solomon
• R Sills
• A Pandiri

Abstract

Introduction: Mitochondria play an important role in cellular energy metabolism. Under xenobiotic stress, free radical generation and subsequent chronic oxidative stress have been implicated in many carcinogenic processes. Experimental Design and Methods: The origin and impact of mitochondrial DNA (mtDNA) alterations in chemical induced carcinogenesis are unclear. We performed ultra-deep whole mtDNA sequencing, whole exome sequencing and mtDNA copy number analysis on the fresh-frozen B6C3F1/N male hepatocellular carcinomas (HCCs) that arose either spontaneously (n=10) or due to 2-year exposure to a genotoxic carcinogen, gingko biloba extract (GBE; n=10) and a non-genotoxic carcinogen, anthraquinone (n=10); age-matched non-tumor controls (n=10) were also included. Results: In total, 25 somatic substitutions were detected in the mitochondrial genome. Mutation signature analysis of the mitochondrial genome demonstrated a similar pattern (A/C to G/T transitions) across all tumor samples. The mtDNA copy number analysis revealed a significant reduction in spontaneous (p=0.0017) and anthraquinone-induced (p=0.0006) HCCs but not in GBE-induced HCCs (p=0.0516). The number of nuclear encoded mitochondrial genes mutations in the GBE-exposed tumors was slightly higher (122 mutations per sample) compared to the number of mutations in the spontaneous (97.4 mutations per sample) or anthraquinone-exposed (91.7 mutations per sample) tumors. Conclusion: Our findings indicate that the endogenous mutational mechanism has greater impact than any other external mutagens in mtDNA and is fundamentally linked to mtDNA replication. Exposure to GBE or anthraquinone may have different mechanisms of action on mitochondrial dysfunction. Impact statement: Unique molecular characterizations of mitochondrial and nuclear DNA could help us better understand the mode of action in chemical carcinogenesis.

Scientific Focus Area: Cancer Biology

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