Association of mutation frequencies across tissue-specific replication timing strata in PCAWG tissue samples and cfDNA from patients in the LUCAS cohort with NSCLC, melanoma, B cell non-Hodgkin lymphoma (BNHL) or no cancer. Replication timing was obtained as the wavelet smoothed transform of the six fraction profile, representing different time points during replication in 1 kb bins from IMR90, NHEK and GM12878 cell lines for analyses of NSCLC, melanoma and BNHL, respectively. The weighted average of the replication timing values was computed in 2.5 Mb bins, followed by grouping of bins into five equal bin sets containing bins with the earliest to latest replication timing. In each bin set, we computed the mutation frequency in tissue at different replication strata using the number of somatic mutations reported by the PCAWG Consortium per Mb of genome and compared this to the single-molecule mutation frequency in plasma using a two-sided Pearson’s correlation. To control for potential systematic variability in measured genome-wide mutational frequencies, we subtracted from both cancer and non-cancer cfDNA samples the single-molecule mutation frequency in each bin set in a separate panel of 20 non-cancer cfDNA samples. Mutation frequencies were then scaled within each sample and mutation type to have a minimum value of zero. NA, not applicable.
