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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 
 Cancer Research and Treatment, Vol.48(1) : 208-215, 2016 
Journal Title
 Cancer Research and Treatment 
Issue Date
CIMP ; Colorectal neoplasms ; KRAS ; Methylation ; p16
PURPOSE: Hypermethylation of the CpG island of p16(INK4a) 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 KRAS mutation 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 KRAS mutation (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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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김남규(Kim, Nam Kyu) ORCID logo https://orcid.org/0000-0003-0639-5632
김태일(Kim, Tae Il) ORCID logo https://orcid.org/0000-0003-4807-890X
노재경(Roh, Jae Kyung)
라선영(Rha, Sun Young) ORCID logo https://orcid.org/0000-0002-2512-4531
박규현(Park, Kyu Hyun)
신상준(Shin, Sang Joon) ORCID logo https://orcid.org/0000-0001-5350-7241
안중배(Ahn, Joong Bae) ORCID logo https://orcid.org/0000-0001-6787-1503
이강영(Lee, Kang Young)
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