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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 29, 2010
Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients
Frank A Sinicrope1, Rafaela L Rego, Kevin C Halling
1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. sinicrope.frank@mayo.edu
Background & Aims:
Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables.
Methods:
Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined.
Results:
MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant.
Conclusions:
DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.
Insights
DNA ploidy and high-frequency microsatellite instability (MSI-H) are independent prognostic markers in colon cancer. Diploidy, a measure of DNA content, emerged as the strongest predictor of better survival for patients with colon cancer.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Genomic instability in colon cancer arises from chromosomal instability (aneuploidy) or defective DNA mismatch repair (MMR).
- High-frequency MSI (MSI-H) is often associated with diploidy, suggesting a potential link between these markers.
Purpose of the Study:
- To investigate whether DNA ploidy and MSI-H status are independent prognostic variables in colon cancer.
- To determine the relative strength of ploidy and MSI-H as prognostic markers.
Main Methods:
- Analysis of 528 stage B2 and C colon cancers for MSI using 11 microsatellite markers.
- Immunostaining for MMR proteins (hMLH1, hMSH2) and p53.
- DNA ploidy analysis by flow cytometry.
- Association of these markers with disease-free and overall survival.
Main Results:
- MSI-H was found in 18% of tumors, with 74% of these being diploid.
- Both MSI-H and diploidy were associated with improved overall survival.
- Diploidy was the strongest independent prognostic marker, outperforming MSI status.
Conclusions:
- DNA ploidy and MSI-H status are independent prognostic variables in colon cancer.
- DNA ploidy is a stronger prognostic marker than MSI status.
- Diploid tumors show better survival outcomes regardless of MSI status.
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