The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer.
ABSTRACT Post-translational histone modifications are known to be altered in cancer tissues, and differences in the histone modification levels have recently been used to predict the clinical outcome in patients with certain types of cancer. In this study, we evaluated the immunohistochemical staining patterns of histone H3 dimethylation and acetylation in metachronous liver metastasis of colorectal carcinomas and examined its correlation with patient prognosis. Double 2 mm core tissue microarrays were made from 54 paraffin-embedded samples of liver metastasis from colorectal adenocarcinoma, and were examined by an immunohistochemical analysis of histone H3 lysine 4 (H3K4) dimethylation, histone, H3 lysine 9 (H3K9) dimethylation and histone H3 lysine 9 (H3K9) acetylation. Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were then examined for correlations with the clinicopathological parameters and clinical outcome. Dimethylation of H3K4 correlated with the tumor histological type (P=0.043), and acetylation of H3K9 correlated with the tumor histological type (P=0.016). In addition, lower levels of H3K4 dimethylation correlated with a poor survival rate (P=0.035). The multivariate survival analysis showed that the H3K4 dimethylation status is an independent prognostic factor for colorectal cancer patients (P=0.011). We suggest that the pattern of histone modification as detected by immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.
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ABSTRACT: BACKGROUND: Remarkable progress has been made in the last decade in new methods for biological measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges, and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, microRNAs (miRNAs), and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g. systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytical and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies.Cancer Epidemiology Biomarkers & Prevention 12/2012; · 4.56 Impact Factor
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ABSTRACT: Object Ependymal tumors are highly variable in clinical and molecular behavior and affect both children and adults. Regarding the paucity of appropriate experimental models, the underlying molecular mechanisms of their behavioral variability are poorly understood. Considering the increasing evidence of epigenetic changes in various tumors, in addition to the preclinical success of epigenetic-based therapeutics in tumors of the CNS, epigenetic study of ependymal tumors is warranted. Methods Using immunohistochemistry, the authors investigated the patterns of global acetylation of lysine position 9 of histone 3 (H3K9Ac), an epigenetic marker of active gene transcription, in 85 ependymal tumors with various WHO grades and clinicopathological characteristics. Results Most of the nuclei in all ependymal tumors were H3K9Ac negative (mean ± SD 65.9% ± 26.5 vs 34.1% ± 26.5% positive, p < 0.0001). Subependymomas had more H3K9Ac-positive nuclei (67.2% ± 10.2%) than myxopapillary ependymomas, ependymomas, and anaplastic ependymomas (p < 0.05). Additionally, intracranial parenchymal tumors had significantly fewer H3K9Ac-positive nuclei (13.1% ± 21.9%) than tumors of other CNS localizations (p < 0.001), and supratentorial ventricular tumors had the highest number of H3K9Ac-positive nuclei (66.4% ± 11.8%) among CNS ependymal tumors (p < 0.0001). The H3K9Ac pattern in ependymal tumors also revealed prognostic significance such that tumors with less than 20% acetylated nuclei had a higher probability of recurrence than tumors with 20% or more acetylated nuclei (p = 0.0327), and recurrent tumors had significantly fewer H3K9Ac-positive nuclei than primary ones (16% ± 22.5% vs. 38% ± 25.8%; p < 0.0001). However, the effect of tumor location on survival of patients was nonsignificant in a multivariate survival analysis, and H3K9 acetylation levels of tumors contributed independently to the survival of patients. In addition, ependymal tumors with more than or equal to 20% H3K9 acetylated cells had lower MIB-1 expression than those with less than 20% H3K9 acetylated cells (p < 0.01). Conclusions Global H3K9Ac contributes independently to the prognosis of patients with ependymal tumors such that tumors with lower H3K9Ac values have a higher probability of recurrence and are more proliferative. Additionally, subependymomas have a higher H3K9Ac profile than other ependymal tumor subclasses, underlining their benign clinical behavior.Journal of Neurosurgery 10/2013; · 3.15 Impact Factor
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ABSTRACT: Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.World Journal of Gastroenterology 04/2014; 20(15):4276-4287. · 2.55 Impact Factor