The IntOGen-mutations platform (http://www.intogen.org/mutations/) summarizes somatic mutations, genes and pathways involved in tumorigenesis. it identifies and visualizes cancer drivers, analyzing 4,623 exomes from 13 cancer sites. it provides support to cancer researchers, aids the identification of drivers across tumor cohorts and helps rank mutations for better clinical decision-making.

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BackgroundChromatin regulatory factors are emerging as important genes in cancer development and are regarded as interesting candidates for novel targets for cancer treatment. However, we lack a comprehensive understanding of the role of this group of genes in different cancer types.ResultsWe have analyzed 4,623 tumor samples from thirteen anatomical sites to determine which chromatin regulatory factors are candidate drivers in these different sites. We identify 34 chromatin regulatory factors that are likely drivers in tumors from at least one site, all with relatively low mutational frequency. We also analyze the relative importance of mutations in this group of genes for the development of tumorigenesis in each site, and in different tumor types from the same site.ConclusionsWe find that, although tumors from all thirteen sites show mutations in likely driver chromatin regulatory factors, these are more prevalent in tumors arising from certain tissues. With the exception of hematopoietic, liver and kidney tumors, as a median, the mutated factors are less than one fifth of all mutated drivers across all sites analyzed. We also show that mutations in two of these genes, MLL and EP300, correlate with broad expression changes across cancer cell lines, thus presenting at least one mechanism through which these mutations could contribute to tumorigenesis in cells of the corresponding tissues.

e Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype.

14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.

Introduction: Cancer is characterized by aberrant patterns of expression of multiple genes believed to be due to not only genetic but also epigenetic changes. The epigenetic changes are communicated through chemical modifications, including modifications of histone proteins. For each histone, multiple histone-modifying enzymes have been discovered in mammals. We found that the expression of genes with histone modifications was highly predictable from the level of expression of the corresponding histone-modifying enzyme. Specifically, expression of genes displaying histone H3 K27 methylation was dependent on EZH2 expression. Method: We analyzed breast cancer tissue arrays for EZH2 expression. Tissue microarrays were constructed from 95 histologically confirmed breast cancer samples. To identify breast cancer subtypes, the tissues were evaluated for the expression of ER, PR, HER2, CK5/6 and EGFR. Staining with vimentin served as a control to monitor the quality of tissue fixation in archival tumors. Breast cancer subtypes were defined as luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, CK5/6+, and/or EGFR+), HER2+/ER- (HER2+, ER-, PR-), and unclassified (negative for all five markers). EZH2 expression was measured by staining using an anti- EZH2 antibody (Invitrogen, cat. #18-7395). Staining quantification was performed independently by two pathologists. Results: The mean age of the patients was 56 years old (SD=15.6). 63.7% of the patients had estrogen receptor positive tumors, 50.6% had progesterone receptor positive tumors, and 21.2% had HER2+ tumors. The distribution of breast cancer subtypes is luminal A (58.9%), luminal B (6.3%), HER2+/ER- (4.2%), basal-like (28.5%), unclassified (2.1%). A majority of the patients had high grade tumors (46.0% grade II and 47.1% grade III). High EZH2 expression was associated with Her2+ and basal-like tumors (P<0.0001). Conclusion: In this cohort, high expression of EZH2 was associated with the most aggressive breast cancer phenotypes and likely reflects increased expression of histone modifying proteins in the tumors. Supported by Grants: NIH R01CA138631 (E.V.B.), R01 CA142996 and P50 CA125183 (O.I.O). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1061. doi:1538-7445.AM2012-1061

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