1. ¹Department of Medical Genetics and Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland
2. ²The Second Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
3. ³The Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland
4. ⁴Department of Pathology, University of Oulu, Finland
5. ⁵Molecular Biology and Biochemistry Research Center (CIBBIM), Vall d'Hebron Hospital Research Institute, Barcelona, Spain

Correspondence: Professor LA Aaltonen, Department of Medical Genetics, Biomedicum Helsinki, Room B520a, PO Box 63, University of Helsinki, Helsinki, Finland 00014. E-mail: lauri.aaltonen@helsinki.fi

⁶These authors contributed equally to this work.

Received 15 February 2006; Revised 18 May 2006; Accepted 23 May 2006; Published online 3 July 2006.

Abstract

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 10^-7), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.