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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

1
Internal medicine, Seoul National University.
2
Department of Internal Medicine, Seoul National University Hospital saewonhan@gmail.com.
3
Department of Pathology, Seoul National University College of Medicine.
4
Genomics R&D, Celemics Inc.
5
Genomic Division, Celemics Inc.
6
Celemics Inc.
7
Department of Chemistry College of Science, Yonsei University.
8
Department of Surgery, Seoul National University College of Medicine.
9
Department of Internal Medicine, Seoul National University Hospital.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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].

CONCLUSIONS:

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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