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

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Abstract

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.

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Authors and Affiliations

  1. 2nd Department of Medicine and Senckenberg Center of Pathology, Johann Wolfgang Goethe University Medical Center, Theodor-Stern-Kai 7, 60590 , Frankfurt a.M., Germany

    Joerg Trojan, Angela Brieger, Nicole Weber, Susanne Kriener & Wolfgang F. Caspary

  2. 2nd Department of Internal Medicine, University Hospital, Homburg/Saar, Germany

    Jochen Raedle, Bernd Kronenberger & Stefan Zeuzem

Authors
  1. Joerg Trojan
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  2. Angela Brieger
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  3. Jochen Raedle
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  7. Wolfgang F. Caspary
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  8. Stefan Zeuzem
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Correspondence to Joerg Trojan.

Additional information

This work was supported by grants from the Johann Wolfgang Goethe University Frankfurt a.M. (F15/01) and the Paul and Ursula Klein Foundation

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Trojan, J., Brieger, A., Raedle, J. et al. BAX and caspase-5 frameshift mutations and spontaneous apoptosis in colorectal cancer with microsatellite instability. Int J Colorectal Dis 19, 538–544 (2004). https://doi.org/10.1007/s00384-004-0597-1

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