p16 hypermethylation and KRAS mutation are independent predictors of cetuximab plus FOLFIRI chemotherapy in patients with metastatic colorectal cancer

Se Hyun Kim, Kyu Hyun Park, Sang Joon Shin, Kang Young Lee, Tae Il Kim, Nam Kyu Kim, Sun Young Rha, Jae Kyung Roh, Joong Bae Ahn

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose Hypermethylation of the CpG island of p16INK4a occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. Materials and Methods Pyrosequencing was used to identify KRASmutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. Results Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRASmutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). Conclusion Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

Original languageEnglish
Pages (from-to)208-215
Number of pages8
JournalCancer Research and Treatment
Volume48
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1

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CpG Islands
Colorectal Neoplasms
Drug Therapy
Mutation
Methylation
irinotecan
p16 Genes
Phenotype
Leucovorin
Fluorouracil
Paraffin
Formaldehyde
Neoplasms
Multivariate Analysis
Logistic Models
Cetuximab
Survival
DNA
thymidine 5'-triphosphate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Se Hyun ; Park, Kyu Hyun ; Shin, Sang Joon ; Lee, Kang Young ; Kim, Tae Il ; Kim, Nam Kyu ; Rha, Sun Young ; Roh, Jae Kyung ; Ahn, Joong Bae. / p16 hypermethylation and KRAS mutation are independent predictors of cetuximab plus FOLFIRI chemotherapy in patients with metastatic colorectal cancer. In: Cancer Research and Treatment. 2016 ; Vol. 48, No. 1. pp. 208-215.
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title = "p16 hypermethylation and KRAS mutation are independent predictors of cetuximab plus FOLFIRI chemotherapy in patients with metastatic colorectal cancer",
abstract = "Purpose Hypermethylation of the CpG island of p16INK4a occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. Materials and Methods Pyrosequencing was used to identify KRASmutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. Results Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6{\%}) and showed significant association with KRASmutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). Conclusion Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.",
author = "Kim, {Se Hyun} and Park, {Kyu Hyun} and Shin, {Sang Joon} and Lee, {Kang Young} and Kim, {Tae Il} and Kim, {Nam Kyu} and Rha, {Sun Young} and Roh, {Jae Kyung} and Ahn, {Joong Bae}",
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p16 hypermethylation and KRAS mutation are independent predictors of cetuximab plus FOLFIRI chemotherapy in patients with metastatic colorectal cancer. / Kim, Se Hyun; Park, Kyu Hyun; Shin, Sang Joon; Lee, Kang Young; Kim, Tae Il; Kim, Nam Kyu; Rha, Sun Young; Roh, Jae Kyung; Ahn, Joong Bae.

In: Cancer Research and Treatment, Vol. 48, No. 1, 01.01.2016, p. 208-215.

Research output: Contribution to journalArticle

TY - JOUR

T1 - p16 hypermethylation and KRAS mutation are independent predictors of cetuximab plus FOLFIRI chemotherapy in patients with metastatic colorectal cancer

AU - Kim, Se Hyun

AU - Park, Kyu Hyun

AU - Shin, Sang Joon

AU - Lee, Kang Young

AU - Kim, Tae Il

AU - Kim, Nam Kyu

AU - Rha, Sun Young

AU - Roh, Jae Kyung

AU - Ahn, Joong Bae

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Purpose Hypermethylation of the CpG island of p16INK4a occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. Materials and Methods Pyrosequencing was used to identify KRASmutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. Results Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRASmutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). Conclusion Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

AB - Purpose Hypermethylation of the CpG island of p16INK4a occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. Materials and Methods Pyrosequencing was used to identify KRASmutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. Results Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRASmutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). Conclusion Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

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