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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hereditary nonpolyposis colorectal cancer (HNPCC) and some sporadic colorectal cancers exhibit microsatellite instability (MSI).
• MSI is associated with inactivating frameshift mutations in genes like BAX and caspase-5 (cas-5), potentially affecting apoptosis.
• Inactivation of pro-apoptotic genes may promote tumor progression by enabling escape from programmed cell death.

Purpose of the Study:

• To investigate the role of BAX and cas-5 inactivation in spontaneous apoptosis in colorectal cancer.
• To compare apoptosis rates in tumors with and without MSI.
• To determine if BAX or cas-5 frameshift mutations influence apoptosis in MSI-positive colorectal cancers.

Main Methods:

• Analysis of 25 MSI colorectal cancers for frameshift mutations in BAX and cas-5 using fluorescence PCR, cloning, and sequencing.
• Assessment of spontaneous apoptosis rates via in situ DNA nick end-labeling.
• Comparison of results with 25 stage-matched microsatellite stable (MSS) colorectal cancers.

Main Results:

• Frameshift mutations in BAX and cas-5 were found in 64% and 48% of MSI colorectal cancers, respectively.
• No BAX or cas-5 mutations were detected in sporadic MSS colorectal cancers.
• MSI tumors demonstrated a significantly higher rate of spontaneous apoptosis compared to MSS tumors (p <0.05).
• The presence of BAX or cas-5 frameshift mutations had a minimal impact on the observed apoptosis rates.

Conclusions:

• Mismatch-repair deficiency itself is associated with elevated spontaneous apoptosis in colorectal cancer.
• Inactivating frameshift mutations in BAX or cas-5 do not further enhance spontaneous apoptosis in MSI-positive colorectal cancers.