Figure 5. Selection and mutational process for mtDNA somatic substitutions.
(A) Truncating mutations (nonsense substitutions and frame-shifting (FS) coding indels) present significantly lower VAF. (B) Change of VAF of mtDNA somatic mutation between primary and metastatic (or late) cancer tissues. (C) Mutational signature for mtDNA across various tumor types. None of the three highlighted mechanisms or nuclear DNA double-strand breaks repair mechanism (BRCA) match with the mtDNA mutational signature. * Only substitutions in protein-coding genes considered. (D) A proposed model of mtDNA mutational process.
Figure 5—figure supplement 1. Number of recurrent substitutions between silent and missense substitutions.
100 sites were randomly selected from silent substitutions (at third base
of triplet codon) and missense substitutions (at first and second base of
triplet codon). No significant difference was observed among these three
groups.
Figure 5—figure supplement 2. Comparison of VAF of protein-truncating mutations (nonsense substitution and indels) across tumor types.
Four tumor types with more than 10 protein-truncating mutations are
shown. Fisher's exact were applied between breast and other tissue
types.
Figure 5—figure supplement 3. Negligible impacts of external mutagens (UV and tobacco smoking) to the somatic mtDNA mutations.
No evidence of UV and tobacco smoking was identified even in melanoma and
lung cancers, respectively. (Left) We compared the proportion of C > T
(and G > A) substitutions in the CpC (GpG) context (mutational
signature for UV [Alexandrov et al.,
2013]) between melanomas and breast cancers (controls). Because
UV shows trivial impact to the nuclear DNA somatic mutations of breast
cancers (Alexandrov et al.,
2013), the vast majority of mtDNA C > T substitutions in the
CpC context from breast cancers were not generated by UV. (Right) We
compared the proportion of C > A (G > T) substitutions between lung
and breast (control) cancers. C > A (G > T) substitutions are
dominantly generated by tobacco smoking. Like UV, the impact of tobacco
smoking to the somatic mutations of breast cancers is trivial (Alexandrov et al., 2013).