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121.
122.
Cai G Xu Y Lu H Shi Y Lian P Peng J Du X Zhou X Guan Z Shi D Cai S 《International journal of colorectal disease》2008,23(4):365-373
Background and aims Chromosomal instability (CIN) and microsatellite instability (MSI) are two major causes of colorectal cancers. Recently, a
percentage of colorectal cancers were found to be neither CIN nor MSI. This study was performed to explore whether microsatellite-
and chromosomal-stable (MACS) colorectal cancers comprise a substantially distinct subtype.
Materials and methods Sixty-nine sporadic colorectal cancers were classified into three subsets according to ploidy and microsatellite instability
status: CIN+, MSI+, and MACS. Clinicopathologic, genetic, and epigenetic differences among these three groups were investigated
by immunohistochemical analysis of p53, APC, hMLH1, and BAX and methylation study of p14
ARF
, hMLH1, p16
INK4a
, MGMT, and MINT1 with methylation-specific polymerase chain reaction.
Results The 69 cases included 49 CIN+, 7 MSI+, and 13 MACS. MACS were found to differ from CIN+ and MSI+ in three aspects. The clinicopathologic
features of MACS were similar to MSI+ but distinguished from CIN+. Comparatively, MACS preferred proximal location and poor
differentiation (p < 0.05). An immunohistochemical study demonstrated that MACS had a lower rate of loss of hMLH1 or BAX protein than MSI+ and less loss of APC protein than CIN+. In an epigenetic aspect, both MACS and MSI+ had a high rate of CpG island methylator phenotype (46.2 and
42.9%). However, they differed in the presence of hMLH1 methylation (7.7 vs 57.1%, p < 0.05). Otherwise, compared with CIN+, MACS had a more frequent CpG island methylator phenotype and MINT1 methylation (p < 0.05) and relatively more common p16
INK4a
methylation with marginal significance (p = 0.056).
Conclusion MACS sporadic colorectal cancers may compose a unique phenotype with distinct clinicopathologic and molecular characteristics.
No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject
of this article. 相似文献
123.
英国生命伦理学家Ruth Chadwick,在牛津大学以优生和基因工程伦理学方面的研究获得博士学位,目前是英国皇家社会科学学会、英国皇家艺术学会和皇家医学会院士。曾主持由欧洲委员会资助的遗传筛查伦理学的EUROSCREEN项目以及基因组学经济和社会研究中心的研究工作,并为法学、英语、传播、哲学间跨学科研究做出了积极贡献。出版发表了一系列关于遗传学、伦理学等方面的书籍和论文,其在《表观遗传学和个体化医学:前景和伦理学问题》的论文中论述了遗传学的发展使个体化医学的发展出现了可能性,并对其是否会引起伦理学问题进行阐述,还对表观遗传学知识融入个体化医学提出了见解。此外,她还回答了相关学术问题。 相似文献
124.
Kandimalla R van Tilborg AA Kompier LC Stumpel DJ Stam RW Bangma CH Zwarthoff EC 《European urology》2012,61(6):1245-1256
Background
DNA methylation markers could serve as useful biomarkers, both as markers for progression and for urine-based diagnostic assays.Objective
Identify bladder cancer (BCa)–specific methylated DNA sequences for predicting pTa-specific progression and detecting BCa in voided urine.Design, setting, and participants
Genome-wide methylation analysis was performed on 44 bladder tumours using the Agilent 244K Human CpG Island Microarray (Agilent Technologies, Santa Clara, CA, USA). Validation was done using a custom Illumina 384-plex assay (Illumina, San Diego, CA, USA) in a retrospective group of 77 independent tumours. Markers for progression were identified in pTa (n = 24) tumours and validated retrospectively in an independent series of 41 pTa tumours by the SNaPshot method (Applied Biosystems, Foster City, CA, USA).Measurements
The percentage of methylation in tumour and urine samples was used to identify markers for detection and related to the end point of progression to muscle-invasive disease with Kaplan-Meier models and multivariate analysis.Results and limitations
In the validation set, methylation of the T-box 2 (TBX2), T-box 3 (TBX3), GATA binding protein 2 (GATA2), and Zic family member 4 (ZIC4) genes was associated with progression to muscle-invasive disease in pTa tumours (p = 0.003). Methylation of TBX2 alone showed a sensitivity of 100%, a specificity of 80%, a positive predictive value of 78%, and a negative predictive value of 100%, with an area under the curve of 0.96 (p < 0.0001) for predicting progression. Multivariate analysis showed that methylation of TBX3 and GATA2 are independent predictors of progression when compared to clinicopathologic variables (p = 0.04 and p = 0.03, respectively). The predictive accuracy improved by 23% by adding methylation of TBX2, TBX3, and GATA2 to the European Organisation for Research and Treatment of Cancer risk scores. We further identified and validated 110 CpG islands (CGIs) that are differentially methylated between tumour cells and control urine. The limitation of this study is the small number of patients analysed for testing and validating the prognostic markers.Conclusions
We have identified four methylation markers that predict progression in pTa tumours, thereby allowing stratification of patients for personalised follow-up. In addition, we identified CGIs that will enable detection of bladder tumours in voided urine. 相似文献125.
126.
127.
Konstantinopoulos PA Vandoros GP Papavassiliou AG 《Cancer chemotherapy and pharmacology》2006,58(5):711-715
Purpose: The fundamental role of epigenetic events in carcinogenesis has resulted in the evolution of epigenetic targeting as a new paradigm in anticancer therapeutics. Aberrant histone deacetylase (HDAC) activity has been documented in many human malignancies resulting in the repression of tumor suppressor genes and promotion of tumorigenesis. FK228, also known as depsipeptide, is a novel, natural, bicyclic tetrapeptide with significant antitumor properties which are mostly mediated by inhibition of HDACs. Results: FK228 induces the expression of genes linked to the inhibition of cell growth, induction of cell differentiation, promotion of apoptotic cell death and inhibition of angiogenesis. Conclusion: Its multitargeting properties, its ability to act on non-histone targets, its clinical activity and its acceptable side-effect profile render FK228 a very promising novel anticancer agent. 相似文献
128.
Objective: Patients with systemic malignancies have substantial quantities of tumor-specific DNA in their plasma which may serve as a potential biomarker for tumor burden. This approach has not been studied in gliomas. Methods: Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status the promoters for p16/INK4a, MGMT, p73, and RARβ within glioma tissue and plasma. Blood was collected prior to craniotomy in 10 patients with glioma. DNA was extracted from tumor and plasma samples and assayed with MSP. Total plasma DNA also was quantified. Tumor-specific plasma DNA was defined as identification of the same methylated promoter (MP) in both tumor and plasma. Results: Total plasma DNA concentration was markedly elevated (mean 6,503 ng/ml, SEM 1,400 ng/ml). Glioma tissue contained methylation of at least one promoter in 9 out of 10 (90 percent) of patients studied. Of these patients, 6 out of 9 (67 percent) demonstrated methylation of at least one of the same promoters in plasma. Five of these had one MP identified in the plasma and one had 2 MP. Overall, glioma-specific plasma DNA was present in plasma of 6 out of 10 (60 percent) of patients. Each MP DNA marker found in the plasma also was present in the intracranial tumor. Conclusions: Patients with high grade gliomas have large amounts of DNA in the plasma. Of these primary brain tumors, 90 percent contained methylated gene promoters, and in over 60 percent of these patients the same methylated promoters present in the tumor also were found in the plasma. This represents the first step to developing a quantitative plasma biomarker that could be used to monitor glioma status. 相似文献
129.
The ways in which epigenetic modifications fix the effects of early environmental events,ensuring sustained responses to transient stimuli,which result in modified gene expression patterns and phenotypes later in life,is a topic of considerable interest.This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics,position and functions of epigenetic marks.Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks,at the global or individual gene level,of environmental stressors in humans and animal models.In parallel,increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes,by highlighting the importance of crosstalk between the different epigenetic marks.A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition,epigenetic processes and long-term illness.The existence of a self-propagating epigenetic cycle has been demonstrated.Moreover,recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult.Despite recent progress,we are still far from understanding how,when and where environmental stressors disturb key epigenetic mechanisms.Thus,identifying the original key marks and their changes throughout development during an individual’s lifetime or over several generations remains a challenging issue. 相似文献
130.