title: Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer.
abstract: Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.
authors.affiliation: Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. h-sugita.srg2@tmd.ac.jp
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sugita
authors.forename: Satoru
authors.initials: S
authors.lastname: Iida
authors.forename: Mikito
authors.initials: M
authors.lastname: Inokuchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Kato
authors.forename: Megumi
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Megumu
authors.initials: M
authors.lastname: Enjoji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kojima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugihara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation / Q000502:physiology; D064550:Death-Associated Protein Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C090121:BNIP3 protein, human; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases