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Open Access Research article

Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin

Manuela Pinheiro1, Terje Ahlquist23, Stine A Danielsen23, Guro E Lind23, Isabel Veiga1, Carla Pinto1, Vera Costa1, Luís Afonso4, Olga Sousa5, Maria Fragoso6, Lúcio Santos7, Rui Henrique49, Paula Lopes4, Carlos Lopes49, Ragnhild A Lothe238 and Manuel R Teixeira139*

Author Affiliations

1 Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

2 Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway

3 Centre for Cancer Biomedicine, University of Oslo, Montebello, 0310 Oslo, Norway

4 Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

5 Department of Radiotherapy, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

6 Department of Oncology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

7 Department of Surgery, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

8 Faculty of Medicine, University of Oslo, Oslo, Norway

9 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Largo Prof. Abel Salazar, 4099-003 Porto, Portugal

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BMC Cancer 2010, 10:587  doi:10.1186/1471-2407-10-587

Published: 27 October 2010

Abstract

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.