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BAX and caspase-5 frameshift mutations and spontaneous apoptosis in colorectal cancer with microsatellite instability.

Trojan J, Brieger A, Raedle J, Weber N, Kriener S, Kronenberger B, Caspary WF, Zeuzem S

2nd Department of Medicine and Senckenberg Center of Pathology, Johann Wolfgang Goethe University Medical Center, Theodor-Stern-Kai 7, 60590 Frankfurt a.M., Germany. trojan@em.uni-frankfurt.de.

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.

Published 13 October 2004 in Int J Colorectal Dis, 19(6): 538-44.
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