Loss of the protective function of telomeres has previously been hypothesized to cause a DNA damage response. Here, we report a genome-wide expression response, the telomerase deletion response (TDR), that occurs when telomeres can no longer be maintained by telomerase. The TDR shares features with other DNA damage responses and the environmental stress response. Unexpectedly, another feature of the TDR is the up-regulation of energy production genes, accompanied by a proliferation of mitochondria. Finally, a discrete set of genes, the ''telomerase deletion signature'', is uniquely up-regulated in the TDR but not under other conditions of stress and DNA damage that have been reported. The telomerase deletion signature genes define new candidates for involvement in cellular responses to altered telomere structure or function.
BackgroundMethylation of CpG islands within the DNA promoter regions is one mechanism that leads to aberrant gene expression in cancer. In particular, the abnormal methylation of CpG islands may silence associated genes. Therefore, using high-throughput microarrays to measure CpG island methylation will lead to better understanding of tumor pathobiology and progression, while revealing potentially new biomarkers. We have examined a recently developed high-throughput technology for measuring genome-wide methylation patterns called mTACL. Here, we propose a computational pipeline for integrating gene expression and CpG island methylation profles to identify epigenetically regulated genes for a panel of 45 breast cancer cell lines, which is widely used in the Integrative Cancer Biology Program (ICBP). The pipeline (i) reduces the dimensionality of the methylation data, (ii) associates the reduced methylation data with gene expression data, and (iii) ranks methylation-expression associations according to their epigenetic regulation. Dimensionality reduction is performed in two steps: (i) methylation sites are grouped across the genome to identify regions of interest, and (ii) methylation profles are clustered within each region. Associations between the clustered methylation and the gene expression data sets generate candidate matches within a fxed neighborhood around each gene. Finally, the methylation-expression associations are ranked through a logistic regression, and their significance is quantified through permutation analysis.ResultsOur two-step dimensionality reduction compressed 90% of the original data, reducing 137,688 methylation sites to 14,505 clusters. Methylation-expression associations produced 18,312 correspondences, which were used to further analyze epigenetic regulation. Logistic regression was used to identify 58 genes from these correspondences that showed a statistically signifcant negative correlation between methylation profles and gene expression in the panel of breast cancer cell lines. Subnetwork enrichment of these genes has identifed 35 common regulators with 6 or more predicted markers. In addition to identifying epigenetically regulated genes, we show evidence of differentially expressed methylation patterns between the basal and luminal subtypes.ConclusionsOur results indicate that the proposed computational protocol is a viable platform for identifying epigenetically regulated genes. Our protocol has generated a list of predictors including COL1A2, TOP2A, TFF1, and VAV3, genes whose key roles in epigenetic regulation is documented in the literature. Subnetwork enrichment of these predicted markers further suggests that epigenetic regulation of individual genes occurs in a coordinated fashion and through common regulators.
A unique microarray-based method for determining the extent of DNA methylation has been developed. It relies on a selective enrichment of the regions to be assayed by target amplification by capture and ligation (mTACL). The assay is quantitatively accurate, relatively precise, and lends itself to high-throughput determination using nanogram amounts of DNA. The measurements using mTACLs are highly reproducible and in excellent agreement with those obtained by sequencing (r = 0.94). In the present work, the methylation status of >145,000 CpGs from 5,472 promoters in 221 samples was measured. The methylation levels of nearby CpGs are correlated, but the correlation falls off dramatically over several hundred base pairs. In some instances, nearby CpGs have very different levels of methylation. Comparison of normal and tumor samples indicates that in tumors, the promoter regions of genes involved in differentiation and signaling are preferentially hypermethylated, whereas those of housekeeping genes remain hypomethylated. mTACL is a platform for profiling the state of methylation of a large number of CpG in many samples in a cost-effective fashion, and is capable of scaling to much larger numbers of CpGs than those collected here.array | technology | tumor
Basal cell adenoma (BCA) of the salivary gland is a rare neoplasm consists of a monomorphic population of basaloid epithelial cells, and it accounts for approximately 1-2 % of all salivary gland tumors. Its most frequent location is the parotid gland. It usually appears as a firm and mobile slow-growing mass. Histologically, isomorphic cells in nests and interlaced trabecules with a prominent basal membrane are observed. In contrast to pleomorphic adenoma, it tends to be multiple and its recurrence rate after surgical excision is high. Due to prognostic implications, differential diagnosis with basal cell adenocarcinoma, adenoid cystic carcinoma and basaloid squamous cell carcinoma is mandatory. We report a case of BCA of the parotid gland. We also review the literature and discuss the diagnosis and management of this rare entity.
<p class="abstract"><strong>Background:</strong> Thyroid enlargement, whether diffuse or in the form of a nodule, leads to a battery of investigations to be done. Fine needle aspiration cytology (FNAC) is usually the first line of investigation but the limitations of cytology are well recognized in the diagnosis of some thyroid malignancies, in particular it is not able to differentiate between follicular adenoma and carcinoma. We conducted a prospective study to assess the role of FNAC in diagnosing the nature of thyroid swelling and comparing its result with histopathology finding.</p><p class="abstract"><strong>Methods:</strong> This was a prospective study conducted on 100 consecutive patients presented with thyroid swelling in department of otorhinolaryngology. </p><p class="abstract"><strong>Results:</strong> The present data show high specificity (96.29%) of FNAC as compared to sensitivity, which came out to be (78.9%). Positive and negative predictive value is 93.75% and 95.23%. This is quite similar to previous studies.</p><p class="p1"><strong>Conclusions:</strong> FNAC has high specificity (96.29%), sensitivity (78.9%), positive predictive value (93.75%), negative predictive value (95.23%) and accuracy (95%) therefore it can be reliably used as initial investigation. A benign FNAC diagnosis should be viewed with caution as false negative results do occur and these patients should be followed up clinico-radiologically for any progression that will require repeated FNAC and/or surgery. </p>
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