Parent-of-origin phasing of somatic mutations shows equal mutation burden between parental genomes in human cancers

Human cancers develop as mutations accumulate independently in the two sets of genetic material inherited from each parent. While local mutation rates can be influenced by factors like DNA sequence, epigenetic modifications, and chromatin structure, it remains unclear if these differences translate into a broader genome-wide impact on mutation accumulation.

Many cancer research methods, such as tracking copy-number gains and analyzing molecular history, rely on the assumption that mutations are acquired symmetrically on both parental genomes. However, this assumption has never been empirically tested.

The study introduces PhaSoMix, a computational framework that exploits genetic differences between the two parental haplotypes in cancer patients who have mixed ancestry. By assigning somatic mutations to their specific parent of origin, PhaSoMix does not require sequencing of either parent or a parent surrogate. When applied to 21 whole-genome datasets from the Pan-Cancer Analysis of Whole Genomes project, PhaSoMix reveals that the burden of mutations is strikingly symmetric between maternal and paternal genomes across various cancer types, genomic annotations, stages of clonal evolution, and different mutational processes.

Even when accounting for uncertainties in phasing and ancestry inference, the asymmetry in mutation burden is confined to a small range of 4-5%.

Simulations suggest that any significant asymmetry in mutation accumulation would substantially compromise estimates of cancer evolution, particularly in the later stages of tumor development. This research provides the first quantitative evidence of equal mutation burden between the two parental genomes in living human cancers. By validating the assumption of symmetric mutation accrual, PhaSoMix offers a crucial foundation for refining cancer evolutionary analyses.