title: Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX.
abstract: BACKGROUND
  Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.
  
  
  RESULTS
  CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (-) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).
  
  
  CONCLUSIONS
  Concurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Cha
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Ye Young
authors.initials: YY
authors.lastname: Rhee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Jeong Mo
authors.initials: JM
authors.lastname: Bae
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyu Joo
authors.initials: KJ
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea ; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
keywords: Colorectal cancer; CpG islands methylator phenotype; FOLFOX; Sex