Extended Data Fig. 4: Age-corrected SBS1 mutation burden in primary and metastatic tumors.

a) Linear regression of the SBS1 mutation burden (y-axis) and patient’s age at biopsy (x-axis) in primary and metastatic cancer across the 23 cancer types. The median trendline and 99% confidence intervals of the linear regression are represented as a solid line and the adjacent shaded area, respectively. The mean fold change, mean SBS1 increase per year and one sided Mann-Whitney p-value are only displayed in cancer types with an age-independent significantly different primary and metastatic distribution. Red labels, significant increase in metastatic tumors. Blue, control cancer types. R_met and R_prim, Pearson correlation coefficient of the metastatic and primary linear regressions, respectively. b) Analogous representation for independent linear regressions for breast cancer subtypes. c) Relative to a) for ploidy corrected SBS1 in the tumor types of interest. d) Relative to a) for ploidy corrected SBS5/40 counts in the tumor types of interest. e) Depiction illustrating the potential effect of an increased cell division rate in metastatic tumors compared to primary and its expected impact on the SBS1 variant allele frequency (VAF) distribution. Partially created BioRender.com. f) Comparison of global SBS1 clonality ratios between primary and metastatic in breast, prostate, kidney renal clear cell, thyroid, colorectal and ovarian serous carcinomas. Boxplots are defined as in Fig. 1. P, two-sided Mann-Whitney p-value. N, number of samples. g) Spearman correlation analysis of the mean SBS1 year burden of primary tumors (y-axis) and the mean metastatic SBS1 fold change (x-axis) across the 15 cancer types with linear association between age and SBS1 accumulation. Vertical error bars represent the 25th and 75th percentile, respectively. Horizontal error bars represent the standard deviation of the mean fold change (metastatic divided by primary) of the SBS1 yearly mutation burden. The median trendline and 99% confidence intervals of the linear regression are represented as a solid line and the adjacent shaded area, respectively. Cancer types with a significantly different SBS1 mutation rate are marked by thicker marker borders and with red labels. Blue labels represent the control cancer types. h) Similar but using SBS1 year mutation rate from ref. ³⁰. To derive vertical and horizontal error bars in panels g) and h) all tumor samples from the primary and metastatic cohorts from panel a) (see Methods for inclusion criteria) were included in the analysis. The number of included samples per cancer type and cohort are available in Supplementary Table 4. Muts, mutations.