Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

Area of Science:

• Genomics
• Cancer Biology
• Mitochondrial Biology

Background:

• Somatic alterations in nuclear genomes of cancers are well-studied.
• The origins and impact of mutations in mitochondrial DNA (mtDNA) during cancer development remain unclear.
• Mitochondria play crucial roles in cellular energy metabolism and apoptosis.

Purpose of the Study:

• To analyze somatic alterations in mtDNA across a large cohort of tumors.
• To characterize the mutational signatures and selective pressures acting on mtDNA in cancer.
• To understand the relationship between mtDNA mutations and cancer progression.

Main Methods:

• Analysis of somatic mtDNA alterations from 1675 tumors.
• Identification and characterization of somatic substitutions.
• Assessment of mutational signatures, strand bias, and selective pressures (neutral vs. negative selection).

Main Results:

• Identified 1907 somatic mtDNA substitutions with a strong replicative strand bias (C > T, A > G on heavy strand).
• Observed a strand-asymmetric mutational signature distinct from nuclear cancer genomes but similar to primate germline mtDNA.
• Found heterogeneity in mtDNA mutations across tumor types, with missense mutations being selectively neutral and truncating mutations under negative selection.

Conclusions:

• The endogenous mutational mechanism has a greater impact on mtDNA than external mutagens.
• mtDNA replication is fundamentally linked to the observed mutational patterns.
• mtDNA mutations exhibit distinct evolutionary trajectories based on their functional impact (neutral drift vs. negative selection).