title: p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Institute for Cancer Research, College of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Kyu Hyun
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kang Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Nam Kyu
authors.initials: NK
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Roh
authors.affiliation: Institute for Cancer Research, College of Medicine, Yonsei University, Seoul, Korea ; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
mesh_terms: D000328:Adult; D000368:Aged; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin
keywords: CIMP; Colorectal neoplasms; KRAS; Methylation; p16