Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin

Dae Won Lee, Sae Won Han, Jeong Mo Bae, Hoon Jang, Hyojun Han, Hyoki Kim, Duhee Bang, Seung Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae You Kim

Research output: Contribution to journalArticle

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 ¼ 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 ¼ 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 ¼ 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.

Original languageEnglish
Pages (from-to)6141-6147
Number of pages7
JournalClinical Cancer Research
Volume25
Issue number20
DOIs
Publication statusPublished - 2019 Oct 15

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oxaliplatin
Tumor Burden
Colorectal Neoplasms
Mutation
Recurrence
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, Dae Won ; Han, Sae Won ; Bae, Jeong Mo ; Jang, Hoon ; Han, Hyojun ; Kim, Hyoki ; Bang, Duhee ; Jeong, Seung Yong ; Park, Kyu Joo ; Kang, Gyeong Hoon ; Kim, Tae You. / Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 20. pp. 6141-6147.
@article{4b71806dcb1942a6a7d9a67a14faa3f0,
title = "Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin",
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 ¼ 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 ¼ 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 ¼ 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.",
author = "Lee, {Dae Won} and Han, {Sae Won} and Bae, {Jeong Mo} and Hoon Jang and Hyojun Han and Hyoki Kim and Duhee Bang and Jeong, {Seung Yong} and Park, {Kyu Joo} and Kang, {Gyeong Hoon} and Kim, {Tae You}",
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Lee, DW, Han, SW, Bae, JM, Jang, H, Han, H, Kim, H, Bang, D, Jeong, SY, Park, KJ, Kang, GH & Kim, TY 2019, 'Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin', Clinical Cancer Research, vol. 25, no. 20, pp. 6141-6147. https://doi.org/10.1158/1078-0432.CCR-19-1105

Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin. / Lee, Dae Won; Han, Sae Won; Bae, Jeong Mo; Jang, Hoon; Han, Hyojun; Kim, Hyoki; Bang, Duhee; Jeong, Seung Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae You.

In: Clinical Cancer Research, Vol. 25, No. 20, 15.10.2019, p. 6141-6147.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin

AU - Lee, Dae Won

AU - Han, Sae Won

AU - Bae, Jeong Mo

AU - Jang, Hoon

AU - Han, Hyojun

AU - Kim, Hyoki

AU - Bang, Duhee

AU - Jeong, Seung Yong

AU - Park, Kyu Joo

AU - Kang, Gyeong Hoon

AU - Kim, Tae You

PY - 2019/10/15

Y1 - 2019/10/15

N2 - 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 ¼ 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 ¼ 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 ¼ 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.

AB - 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 ¼ 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 ¼ 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 ¼ 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.

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U2 - 10.1158/1078-0432.CCR-19-1105

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