title: Methylated BNIP3 gene in colorectal cancer prognosis.
abstract: The DNA methylation of apoptosis-related genes in various cancers contributes to the disruption of the apoptotic pathway and results in resistance to chemotherapeutic agents. Irinotecan (CPT-11) is one of the key chemotherapy drugs used to treat metastatic colorectal cancer (CRC). However, a number of metastatic CRC patients do not benefit from this drug. Thus, the identification of molecular genetic parameters associated with the response to CPT-11 is of interest. To identify apoptosis-related genes that may contribute to CPT-11 resistance, microarray analysis was conducted using colon cancer cells in which 5-aza-2'deoxycytidine (DAC) enhanced sensitivity to CPT-11. Microarray analysis identified 10 apoptosis-related genes that were up-regulated following treatment with DAC. Among the genes, Bcl-2/adenovirus E1B 19 kDa protein interacting protein 3 (BNIP3), a Bcl-2 family pro-apoptotic protein, was identified as being involved in CPT-11 resistance following methylation of its promoter. An analysis of 112 primary CRC cases revealed that approximately 58% of cases showed BNIP3 methylation, and that patients with methylation exhibited a poorer outcome compared to those without methylation. In addition, in 30 patients who received first-line CPT-11 chemotherapy, patients with methylation exhibited resistance to chemotherapy compared to patients with no methylation. The results suggest that methylation of BNIP3 is a predictive factor in the prognosis and response to CPT-11 treatment in CRC patients.
authors.affiliation: Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Shimizu
authors.forename: Satoru
authors.initials: S
authors.lastname: Iida
authors.forename: Megumi
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Enomoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugihara