BACKGROUND AND AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic colorectal cancers are characterized by microsatellite instability (MSI) and inactivating frameshift mutations of target genes. Inactivation of BAX, caspase-5 ( cas-5), and other genes coding for pro-apoptotic proteins might contribute to tumor progression by enhancing escape from apoptosis. The aim of this study was to further characterize the role of BAX and cas-5 inactivation for spontaneous apoptosis. METHODS: Twenty-five colorectal cancers with MSI were analyzed for frameshift mutations in the BAX (G)8 and cas-5 (A)10 tract by fluorescence PCR, cloning, and sequencing. The rate of spontaneous apoptosis was examined by in situ DNA nick end-labeling. The results were compared with 25 stage-matched microsatellite stable (MSS) colorectal cancers. RESULTS: In colorectal cancer with MSI frameshift mutations in BAX and cas-5 were present in 16 of 25 (64%) and in 12 of 25 (48%) tumors, respectively, whereas neither mutant BAX nor cas-5 alleles were detected in all stage-matched sporadic MSS colorectal cancer. Tumors with MSI showed a higher apoptotic rate than MSS tumors (2.5+/-1.0 vs. 2.1+/-0.7; p <0.05), whereas the presence of BAX or cas-5 frameshift mutations had only minor influence on this finding (2.4+/-1.1% and 2.5+/-0.9%, respectively). CONCLUSION: Mismatch-repair deficiency itself is associated with increased spontaneous apoptosis, not further accelerated by either inactivating BAX or cas-5 frameshift mutations.
BACKGROUND AND AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic colorectal cancers are characterized by microsatellite instability (MSI) and inactivating frameshift mutations of target genes. Inactivation of BAX, caspase-5 ( cas-5), and other genes coding for pro-apoptotic proteins might contribute to tumor progression by enhancing escape from apoptosis. The aim of this study was to further characterize the role of BAX and cas-5 inactivation for spontaneous apoptosis. METHODS: Twenty-five colorectal cancers with MSI were analyzed for frameshift mutations in the BAX (G)8 and cas-5 (A)10 tract by fluorescence PCR, cloning, and sequencing. The rate of spontaneous apoptosis was examined by in situ DNA nick end-labeling. The results were compared with 25 stage-matched microsatellite stable (MSS) colorectal cancers. RESULTS: In colorectal cancer with MSI frameshift mutations in BAX and cas-5 were present in 16 of 25 (64%) and in 12 of 25 (48%) tumors, respectively, whereas neither mutant BAX nor cas-5 alleles were detected in all stage-matched sporadic MSS colorectal cancer. Tumors with MSI showed a higher apoptotic rate than MSS tumors (2.5+/-1.0 vs. 2.1+/-0.7; p <0.05), whereas the presence of BAX or cas-5 frameshift mutations had only minor influence on this finding (2.4+/-1.1% and 2.5+/-0.9%, respectively). CONCLUSION: Mismatch-repair deficiency itself is associated with increased spontaneous apoptosis, not further accelerated by either inactivating BAX or cas-5 frameshift mutations.
Authors: A Riccio; L A Aaltonen; A K Godwin; A Loukola; A Percesepe; R Salovaara; V Masciullo; M Genuardi; M Paravatou-Petsotas; D E Bassi; B A Ruggeri; A J Klein-Szanto; J R Testa; G Neri; A Bellacosa Journal: Nat Genet Date: 1999-11 Impact factor: 38.330
Authors: W Liu; X Dong; M Mai; R S Seelan; K Taniguchi; K K Krishnadath; K C Halling; J M Cunningham; L A Boardman; C Qian; E Christensen; S S Schmidt; P C Roche; D I Smith; S N Thibodeau Journal: Nat Genet Date: 2000-10 Impact factor: 38.330
Authors: R Dolcetti; A Viel; C Doglioni; A Russo; M Guidoboni; E Capozzi; N Vecchiato; E Macrì; M Fornasarig; M Boiocchi Journal: Am J Pathol Date: 1999-06 Impact factor: 4.307
Authors: J Yin; D Kong; S Wang; T T Zou; R F Souza; K N Smolinski; P M Lynch; S R Hamilton; H Sugimura; S M Powell; J Young; J M Abraham; S J Meltzer Journal: Hum Mutat Date: 1997 Impact factor: 4.878
Authors: J R Jass; K A Do; L A Simms; H Iino; C Wynter; S P Pillay; J Searle; G Radford-Smith; J Young; B Leggett Journal: Gut Date: 1998-05 Impact factor: 23.059
Authors: Pia Alhopuro; Denis Phichith; Sari Tuupanen; Heli Sammalkorpi; Miranda Nybondas; Juha Saharinen; James P Robinson; Zhaohui Yang; Li-Qiong Chen; Torben Orntoft; Jukka-Pekka Mecklin; Heikki Järvinen; Charis Eng; Gabriela Moeslein; Darryl Shibata; Richard S Houlston; Anneke Lucassen; Ian P M Tomlinson; Virpi Launonen; Ari Ristimäki; Diego Arango; Auli Karhu; H Lee Sweeney; Lauri A Aaltonen Journal: Proc Natl Acad Sci U S A Date: 2008-04-07 Impact factor: 11.205