The clonal composition of a malignant tumor strongly depends on cellular dynamics
influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to
identify founder mutations leading to subsequent boosts in mutation load. The overall
mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation
status of DNA-repair genes. The number of mutations was first determined across all
patients and the proportion of genes having mutation in each percentile was ranked.
Early mutations in DNA repair genes preceding a mutational expansion were designated
as founder mutations. Survival analysis for gene expression was performed using microarray
data with available relapse-free survival. Of the 180 genes involved in DNA repair,
the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18),
SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors
compared to normal samples, and higher expression led to longer relapse-free survival
in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational
load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon
treatments, the mutational load exposed a significant two-fold increase. Our results
suggest PRKDC as a new key gene driving tumor heterogeneity.