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Clin Cancer Res. 2019 Jul 8. pii: clincanres.1105.2019. doi: 10.1158/1078-0432.CCR-19-1105. [Epub ahead of print]

Tumor Mutation Burden and Prognosis in Colorectal Cancer Patients Treated with Adjuvant Fluoropyrimidine and Oxaliplatin.

Author information

Internal medicine, Seoul National University.
Department of Internal Medicine, Seoul National University Hospital
Department of Pathology, Seoul National University College of Medicine.
Genomics R&D, Celemics Inc.
Genomic Division, Celemics Inc.
Celemics Inc.
Department of Chemistry College of Science, Yonsei University.
Department of Surgery, Seoul National University College of Medicine.
Department of Internal Medicine, Seoul National University Hospital.



Recent sequencing studies revealed that a subset of colorectal cancer harbors significantly higher number of somatic mutations. These hypermutated tumors show distinct clinico-pathological features. However, the prognostic impact of the hypermutated tumors is not clearly established.


We analyzed tumor mutation burden (TMB) from targeted next-generation sequencing data of 40 major genes in 516 colorectal cancer patients. TMB was defined as total number of non-synonymous mutations per tumor. Cutoff value for TMB-high was chosen which best discriminated relapse-free survival (RFS) using the Contal and O'Quigley method.


In the TCGA data, mutation count of the selected 40 genes reflected the whole exome mutation burden (Pearson correlation 0.873, p < 0.001). In our patient cohort, 8 or more mutation in the 40 genes was defined as TMB-high, which best discriminated RFS. A total of 55 patients (10.7%) had TMB-high. TMB-high tumors were more frequently found in proximal location (63.6%), had higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared to TMB-low. Most importantly, TMB-high was associated with better 5-year RFS compared to TMB-low (96.3% vs 79.8%, p=0.005). Although there was significant overlap between TMB-high and MSI-H, MSI-H status was not significantly associated with RFS. Multivariate analysis revealed TMB-high as an independent positive prognostic factor for RFS [adjusted hazard ratio 0.16 (95% confidence interval 0.04-0.66), p=0.011].


TMB-high is associated with better prognosis in colorectal cancer patients treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

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