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Background  Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC).    Methods  A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis.    Results  Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related  ATM  or  BRCA2  somatic mutations or non- TP53, APC  somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank  p -value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of  APC ,  KRAS  and  APC ,  BRCA2  sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in  BRCA2 , such as  TP53  somatic mutations, affected recurrence-free survival.    Conclusions  According to the evolution model, DNA damage response (DDR)-related  ATM  or  BRCA2  somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12885-021-07926-1.

bmc cancer

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy