title: The cellular level of histone H3 lysine 4 dimethylation correlates with response to adjuvant gemcitabine in Japanese pancreatic cancer patients treated with surgery.
abstract: BACKGROUND
  To search for biomarkers identifying pancreatic cancer patients likely to benefit from adjuvant gemcitabine chemotherapy, we investigated the status of several histone modifications in pancreatic tumors and their relationship to clinicopathological features and outcomes.
  
  
  METHODS
  Sixty one pancreatic cancer patients, primarily treated by surgical removal of tumors, were involved in the study. Thirty patients completed postoperative adjuvant gemcitabine, and in 31 it was discontinued. Tumor specimens were examined using immunohistochemistry for di- and tri-methylation of histone H3 lysine 4 (H3K4me2 and H3K4me3), dimethylation and acetylation of histone H3 lysine 9 (H3K9me2 and H3K9ac), and acetylation of histone H3 lysine 18 (H3K18ac). Positive tumor staining for each histone modification was used to classify patients into low- and high-staining groups, which were examined for relationships to clinicopathological features and clinical outcomes.
  
  
  RESULTS
  High expression of H3K4me3 was related to the well and moderately differentiated tumor histological type (p = 0.012) and low expression of H3K4me2 was related to the presence of perineural invasion (p = 0.007). No cellular histone modifications were associated with overall or disease-free survival of patients as a whole. In the subgroup analyses, a low level of H3K4me2 was significantly associated with worse disease free survival in patients that completed adjuvant gemcitabine (p = 0.0239). Univariate and multivariate hazard models also indicated that a low level of H3K4me2 was a significant independent predictor of disease-free survival (p = 0.007).
  
  
  CONCLUSIONS
  H3K4me2 was found to be a predictor of response to adjuvant gemcitabine in Asian patients with pancreatic cancer.
authors.affiliation: Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku, Yokohama, Kanagawa-ken 241-0815, Japan. twgiraud@gmail.com
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Morinaga
authors.forename: M
authors.initials: M
authors.lastname: Akaike
authors.forename: M
authors.initials: M
authors.lastname: Numata
authors.forename: H
authors.initials: H
authors.lastname: Tamagawa
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Shiozawa
authors.forename: S
authors.initials: S
authors.lastname: Ohkawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kameda
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000601:surgery*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D006657:Histones; D003841:Deoxycytidine; D008239:Lysine; D000093542:Gemcitabine