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Talk Title:

Leveraging mass balance and long DNA molecules to study structural variant mutational processes in cancer

Abstract:

Genome structure, like other physical phenomena, obeys the simple principle of mass balance. I will show how we can apply this principle algorithmically to assess what structural variants (SVs) are missing from short-read whole genomes. These include neotelomeres and footprints of viral-driven chromosomal instability. We can further use mass balance to rigorously demonstrate the extent with which aberrant homologous recombination (HR) shapes cancer genome structure, which we validate with long-read and linked-read whole genome sequencing. We next extend this principle to tumors defective in DNA repair to uncover new SV scars of HR deficiency. Leveraging the ability of long molecules to resolve somatic SV phase, we solve a long-standing paradox in the HR deficiency field linking the chromosomal-scale aberrations observed in repair deficient cells to BRCA1- and BRCA2-deficiency specific base-level alterations. These findings have implications for backup repair pathways in HR deficient tumors and provide additional ingredients for whole genome sequencing biomarkers with near-term clinical applicability.