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Frequent loss of SMAD4/DPC4 protein in colorectal cancers

¹ Department of Medical Genetics and Department of Pathology, Haartman Institute, PO Box 63, FIN-00014 University of Helsinki, Finland
² Department of Medical Genetics, Haartman Institute, PO Box 63, FIN-00014 University of Helsinki, Finland
³ Finnish Red Cross Blood Transfusion Service, Kivihaantie 7, FIN-00310 Helsinki, Finland
⁴ Second Department of Surgery, Helsinki University Central Hospital, PO Box 340, FIN-00029 Helsinki, Finland
⁵ Ludwig Institute for Cancer Research, PO Box 595, S-751 24 Uppsala, Sweden
⁶ Department of Pathology, Haartman Institute, PO Box 63, FIN-00014 University of Helsinki, Finland
⁷ Department of Medical Genetics, Haartman Institute, PO Box 63, FIN-00014 University of Helsinki, Finland, and Department of Oncology, Helsinki University Central Hospital, PO Box 180, FIN-00029 Helsinki, Finland

Correspondence to:
Dr L A Aaltonen, Department of Medical Genetics, Haartman Institute, PO Box 63, FIN-00014 University of Helsinki, Finland;
lauri.aaltonen{at}helsinki.fi.

Background and aims: Loss of DNA sequences from chromosome 18q21 is a major genetic change in colorectal tumorigenesis. Multiple genes have been identified in this area. One of these, DPC4 (deleted in pancreatic cancer 4, also known as SMAD4), is mutated in a minor subset of colorectal carcinomas as well as in germlines of humans predisposed to colon tumours.

Patients and methods: The involvement of SMAD4 in sporadic colorectal neoplasia was evaluated by immunohistochemistry in 53 unselected cases and 27 cases displaying microsatellite instability.

Results: SMAD4 expression was absent in 20 of 53 (38%) unselected colorectal carcinomas, and reduced in another 15 (28%) cases. However, 26 of 27 cancers displaying microsatellite instability and TGF-ßIIR mutations were positive for SMAD4 immunostaining.

Conclusions: Loss of SMAD4 expression may play a more prominent role in colon cancer than anticipated based on genetic evidence, but not in mutator phenotype tumours.

Keywords: SMAD4; DPC4; colorectal carcinoma; immunohistochemistry

Abbreviations: MSI, microsatellite instability; LOH, loss of heterozygosity; RT-PCR, reverse transcription-polymerase chain reaction; TGF-ßIIR, transforming growth factor ß type II receptor