Figure 3. Clonal evolution of CH mutations under the selective pressure of cancer therapy.

(A) Change in VAF for CH mutations from initial to follow-up sequencing for patients stratified by type of therapy received during the follow-up period. XRT, external beam radiation. (B) Change in growth rate for DDR and non-DDR CH mutations among those who received XRT (n=167) or cytotoxic therapy (n=285) during the follow-up period. Shown are the p-values generated from t-tests comparing the growth rate of CH mutations among patients exposed to either of these therapies compared to untreated patients. (C) Change in growth rate for specific CH mutations stratified by whether patients received cytotoxic or radiation therapy (n=268) or no therapy (n=177) during the follow-up period. Shown are the FDR-corrected p-values (q-value) from a t-test comparing the growth rate of mutations in treated and untreated patients. (D) Change in growth rate for DDR and non-DDR CH mutations stratified by tertile of cumulative exposure to cytotoxic therapy and XRT. Shown are the p-values for a trend test for increasing growth rate of CH with increasing tertile of therapy exposure using generalized linear regression adjusted for age, gender and smoking. Shaded bands indicate interquartile ranges. Intra-subject competition between DDR and non-DDR CH mutations. Connecting lines show the difference in growth rate between DDR vs. other genes in patients who received XRT or cytotoxic therapy vs. those who did not receive such therapy during the follow-up period. A paired t-test was used to test for significance in the difference between growth rates of DDR and non-DDR CH mutations within individuals. All p-values are two-sided.