The Histone Methyltransferase and Putative Oncoprotein MMSET Is Overexpressed in a Large Variety of Human Tumors

Abstract

PURPOSE: Multiple myeloma SET (Suppressor of variegation, Enhancer of zeste, and Trithorax) domain (MMSET) is a histone lysine methyltransferase deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation and poor prognosis. With the aim of understanding, if MMSET can be involved in other types of cancer we investigated the expression of MMSET protein in different types of human tumors. EXPERIMENTAL DESIGN: A monoclonal antibody against MMSET was developed and immunohistochemical staining of tissue microarrays (TMA) containing a large number of tumor samples (n = 3774) and corresponding normal tissues (n = 904) was carried out. Further validations of MMSET expression were carried out on independent, tumor-specific sets of TMAs for urinary bladder (n = 1293) and colon cancer (n = 1206) with corresponding clinicopathological data and long-term follow-up. RESULTS: MMSET protein was highly expressed in different tumor types compared to normal counterparts. Particular frequent and/or high MMSET expression was found in carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, tumors of the urinary bladder, female genitals, and skin. In bladder cancer, MMSET expression correlated with tumor aggressiveness. In contrast, MMSET expression was associated with good prognostic factors in colon cancer and was more pronounced in early stages of colon carcinogenesis (dysplasias) than in adenocarcinomas. However, colon cancer patients with high MMSET levels showed a worse 5-year survival. CONCLUSIONS: Our data suggest that MMSET has a broader role in cancer than previously anticipated, and further analysis might qualify it as a prognostic marker and a target for the development of therapy against several types of cancer.