title: CpG island methylation of BNIP3 predicts resistance against S-1/CPT-11 combined therapy in colorectal cancer patients.
abstract: Aberrant gene methylation is frequently observed in various cancers and plays an important role in carcinogenesis, cancer progression and drug responsiveness. The aim of this study is to identify colorectal cancer specific gene methylation determining chemosensitivity to S-1/CPT-11 therapy. The gene methylation of CHFR, p16, RUNX3, E-cadherin, MGMT, hMLH1, ABCG2, UGT1A1 and BNIP3 genes were analyzed in 27 colorectal cancer tissues by quantitative methylation-specific PCR (q-MSP). All 27 patients were postoperatively treated by S-1/CPT-11 therapy targeting the metastatic lesion and the recurrent tumor. Thereafter, the patients were divided into a responder group (RG) or a non-responder group (NRG) according to the effect of the chemotherapy. There were 13 cases of RG (48.1%) and 14 cases of NRG (51.9%). The methylation level in CHFR, RUNX3 and BNIP3 was significantly higher in cancer lesions in comparison to the non-cancerous lesion. Only methylation of the BNIP3 gene was significantly higher in primary cancer tissue of the NRG than the RG. The correlation between the BNIP3 methylation status and time to progression (TTP) suggested that the low methylation group (n=16) resulted in a significantly longer TTP, in comparison to the high methylation group (n=11; P=0.004). The methylation level of BNIP3 showed a significant inverse correlation with the mRNA expression suggesting the DNA methylation suppressed BNIP3 expression (r=-0.466, P=0.021). In conclusion, BNIP3 gene methylation is a possible marker predicting a poor response to the S-1/CPT-11 combined therapy in colorectal cancer.
authors: Department of Surgery, Saga University Faculty of Medicine, Nabeshima, Saga, Japan.
authors: Masatsugu
authors: M
authors: Hiraki
authors: Yoshihiko
authors: Y
authors: Kitajima
authors: Yuji
authors: Y
authors: Nakafusa
authors: Jun
authors: J
authors: Nakamura
authors: Kazuyoshi
authors: K
authors: Hashiguchi
authors: Kenji
authors: K
authors: Sumi
authors: Hirokazu
authors: H
authors: Noshiro
authors: Kohji
authors: K
authors: Miyazaki
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D005641:Tegafur / Q000008:administration & dosage*
chemical_list: C090121:BNIP3 protein, human; D004338:Drug Combinations; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000077146:Irinotecan; D002166:Camptothecin