Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of f6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational ''hotspots,'' which alter Arg residues (Arg 465 and Arg 479 ) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

Purpose: The forkhead box transcription factor FoxP3 is specifically expressed in T cells with regulatory properties (Treg). Recently, high numbers of Treg were described to be associated with poor survival in different malignancies. The aim of the presented study was determine the prognostic effect of FoxP3 mRNA expression (reflecting the tissue content of Treg) in ovarian carcinoma and its relation with cytokines, such as IFN-g. Experimental Design: Total RNA was isolated from 99 ovarian carcinoma and from 14 healthy ovarian biopsies. Real-time PCR for FoxP3 was done and correlated with IFN-g-, CD3-, IRF-1-, SOCS-1-, HER-2-, and iNOS expression as well as patients'outcome.The mRNA data was corroborated by FoxP3 immunohistochemistry. Results: Quantitation of FoxP3 expression identified a patient subgroup (>81th percentile), which is characterized by a significantly worse prognosis in terms of overall survival (27.8 versus 77.3 months, P = 0.0034) and progression-free survival (18 versus 57.5 months; P = 0.0041). FoxP3 expression correlated with IFN-g, IRF-1, and CD3 expression. High FoxP3 expression represents an independent prognostic factor for overall survival (P = 0.004) and progression-free survival (P = 0.004). Conclusions: High expression levels of FoxP3 might represent a surrogate marker for an immunosuppressive milieu contributing to tumor immune escape. Strategies selectively depleting Treg might improve the antitumor activity of endogenously arising tumor-reactiveTcells and immunotherapies using vaccines or antibodies.Cancer patients can harbor significant numbers of CD8 and CD4 T cells specific for tumor antigens. In most cases, tumorreactive T cells fail to eradicate the tumor in vivo because they seem to be actively maintained in an unresponsive state. Several immune-evasion strategies of malignant tumors have been described thus far (reviewed in ref. 1). Recently, regulatory T cells (Treg), which are characterized by coexpression of CD4 and CD25, have also been attributed to contribute to cancer-related immunosuppression (2 -5). Treg represent 5% to 10% of total CD4 + T cells and are crucial for the repression of autoimmune disorders and transplant rejection (6). The activation of Treg is antigen specific; however, inhibition of CD4 + and CD8 + T cells seems to be antigen nonspecific. Very recent evidence showed that Treg abrogate CD8 + T cell -mediated tumor rejection in a transforming growth factor-h -dependent manner (7). The suggestion of a role for Treg in cancer-induced immunosuppression in humans arises from the observation that patients suffering from a variety of cancer types have an enlarged pool of Treg in the peripheral blood, tumor-draining lymph nodes, and in the tumor itself (8 -12). Exact characterization of Treg has been hampered by the lack of specific cell surface markers. The observation that autoimmune diseases occur in both humans and mice lacking functional FoxP3 (13) indicates that this transcription factor plays a crucial role in the regulation of Treg function. ...