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Updated: Jun 7, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according
Manuela Pinheiro1, Terje Ahlquist, Stine A Danielsen
1Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.
Background:
Only a few studies have addressed the molecular pathways specifically involved in carcinogenesis of the distal colon and rectum. We aimed to identify potential differences among genetic alterations in distal colon and rectal carcinomas as compared to cancers arising elsewhere in the large bowel.
Methods:
Constitutional and tumor DNA from a test series of 37 patients with rectal and 25 patients with sigmoid carcinomas, previously analyzed for microsatellite instability (MSI), was studied for BAX, IGF2R, TGFBR2, MSH3, and MSH6 microsatellite sequence alterations, BRAF and KRAS mutations, and MLH1 promoter methylation. The findings were then compared with those of an independent validation series consisting of 36 MSI-H carcinomas with origin from each of the large bowel regions. Immunohistochemical and germline mutation analyses of the mismatch repair system were performed when appropriate.
Results:
In the test series, IGFR2 and BAX mutations were present in one and two out of the six distal MSI-H carcinomas, respectively, and no mutations were detected in TGFBR2, MSH3, and MSH6. We confirmed these findings in the validation series, with TGFBR2 and MSH3 microsatellite mutations occurring less frequently in MSI-H rectal and sigmoid carcinomas than in MSI-H colon carcinomas elsewhere (P = 0.00005 and P = 0.0000005, respectively, when considering all MSI-carcinomas of both series). No MLH1 promoter methylation was observed in the MSI-H rectal and sigmoid carcinomas of both series, as compared to 53% found in MSI-H carcinomas from other locations (P = 0.004). KRAS and BRAF mutational frequencies were 19% and 43% in proximal carcinomas and 25% and 17% in rectal/sigmoid carcinomas, respectively.
Conclusion:
The mechanism and the pattern of genetic changes driving MSI-H carcinogenesis in distal colon and rectum appears to differ from that occurring elsewhere in the colon and further investigation is warranted both in patients with sporadic or hereditary disease.
Insights
Genetic alterations in distal colon and rectal cancers differ from those in the rest of the large bowel. These findings suggest distinct molecular pathways drive MSI-H carcinogenesis in these regions.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Limited research exists on molecular pathways in distal colon and rectal carcinogenesis.
- Understanding genetic alterations in these specific cancer types is crucial for targeted therapies.
Purpose of the Study:
- To identify differences in genetic alterations between distal colon/rectal carcinomas and those in other parts of the large bowel.
- To investigate specific molecular pathways involved in MSI-H carcinogenesis in the distal colorectum.
Main Methods:
- Analyzed microsatellite sequence alterations (BAX, IGF2R, TGFBR2, MSH3, MSH6), BRAF/KRAS mutations, and MLH1 promoter methylation in patient DNA.
- Compared genetic findings between test and validation series of MSI-H carcinomas from different large bowel regions.
- Utilized immunohistochemical and germline mutation analyses of the mismatch repair system.
Main Results:
- TGFBR2 and MSH3 microsatellite mutations were less frequent in MSI-H rectal/sigmoid carcinomas compared to other MSI-H colon carcinomas.
- MLH1 promoter methylation was absent in MSI-H rectal/sigmoid carcinomas, unlike 53% in MSI-H carcinomas from other locations.
- KRAS and BRAF mutation frequencies varied between proximal and distal large bowel carcinomas.
Conclusions:
- The genetic changes driving MSI-H carcinogenesis in the distal colon and rectum appear distinct from those in the proximal colon.
- Further research is needed to elucidate these differences in both sporadic and hereditary cases.
- These findings may inform future diagnostic and therapeutic strategies for distal colorectal cancers.
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