Dae-Won Lee 1 , Sae-Won Han 2,3 , Jeong Mo Bae 4 , Hoon Jang 5 , Hyojun Han 5 , Hyoki Kim 5 , Duhee Bang 6 , Seung-Yong Jeong 7 , Kyu Joo Park 7 , Gyeong Hoon Kang 4 , Tae-You Kim 1,3,8 Show Affiliations »
Abstract
PURPOSE: Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic 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 patients with colorectal cancer. TMB was defined as total number of nonsynonymous mutations per tumor. Cutoff value for TMB-high was chosen by 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 mutations 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 a proximal location (63.6%) and had a higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared with TMB-low. Most importantly, TMB-high was associated with better 5-year RFS compared with 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 HR, 0.16 (95% confidence interval, 0.04-0.66), P = 0.011]. CONCLUSIONS: TMB-high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. ©2019 American Association for Cancer Research.
PURPOSE: Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic 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 patients with colorectal cancer . TMB was defined as total number of nonsynonymous mutations per tumor . Cutoff value for TMB -high was chosen by 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 mutations 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 a proximal location (63.6%) and had a higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared with TMB -low. Most importantly, TMB -high was associated with better 5-year RFS compared with 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 HR, 0.16 (95% confidence interval, 0.04-0.66), P = 0.011]. CONCLUSIONS: TMB -high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. ©2019 American Association for Cancer Research.
Entities: Chemical
Disease
Species
Year: 2019
PMID： 31285374 DOI： 10.1158/1078-0432.CCR-19-1105
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531