S. Tyekucheva

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Isad Saric

University of Sarajevo

Ir. Dr. Ahmad Khairi Abdul Wahab, PhD, CEng (UK)

University of Malaya, Malaysia

Harijono Djojodihardjo

Institut Teknologi Bandung

Umit Unver

Yalova University

Arife Karadağ

Ege University

Lynn Conway

University of Michigan

Md. Irteza Hossain

International University Of Business Agriculture and Technology(IUBAT)

Ernest Onuiri

Babcock University

Mark Zwolinski

University of Southampton

Giuseppe Nicosia

University of Cambridge

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Papers by S. Tyekucheva

Stress-Related Signaling Pathways in Lethal and Non-Lethal Prostate Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 21, 2015

Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We a... more Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and non-lethal disease. We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n=150; n=82 with normal) and the Health Professionals Follow-Up Study (n=254; n=120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome, and to biomarkers as secondary outcomes. Differential mRNA expression of genes within the adrenergic (p=0.001), glucocorticoid (p<0.0001), serotoninergic (p=0.0019), a...

Molecular Differences in Transition Zone and Peripheral Zone Prostate Tumors

Carcinogenesis, Jan 13, 2015

Prostate tumors arise primarily in the peripheral zone of the prostate, but 20-30% arise in the t... more Prostate tumors arise primarily in the peripheral zone of the prostate, but 20-30% arise in the transition zone. Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs), and found that tumors that molecularly resembled transition zone tumors showed lower mortality (p=0.09) that was explained by lower Gleason scores (p=0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on approximately 6000 genes. We had previously observe...

Integrating diverse genomic data using gene sets

Genome Biology, 2011

We introduce and evaluate data analysis methods to interpret simultaneous measurement of multiple... more We introduce and evaluate data analysis methods to interpret simultaneous measurement of multiple genomic features made on the same biological samples. Our tools use gene sets to provide an interpretable common scale for diverse genomic information. We show we can detect genetic effects, although they may act through different mechanisms in different samples, and show we can discover and validate important disease-related gene sets that would not be discovered by analyzing each data type individually.

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Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

by S. Tyekucheva and David Shteynberg

Nature, 2004

Strong and Weak Male Mutation Bias at Different Sites in the Primate Genomes: Insights from the Human-Chimpanzee Comparison

Molecular Biology and Evolution, 2005

Male mutation bias is a higher mutation rate in males than in females thought to result from the ... more Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germ line cell divisions in males. If errors in DNA replication cause most mutations, then the magnitude of male mutation bias, measured as the male-to-female mutation rate ratio (a), should reflect the relative excess of male versus female germ line cell divisions. Evolutionary rates averaged among all sites in a sequence and compared between mammalian sex chromosomes were shown to be indeed higher in males than in females. However, it is presently unknown whether individual classes of substitutions exhibit such bias. To address this issue, we investigated male mutation bias separately at non-CpG and CpG sites using human-chimpanzee whole-genome alignments. We observed strong male mutation bias at non-CpG sites: a in the X-autosome comparison was ;6-7, which was similar to the male-to-female ratio in the number of germ line cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: a in the X-autosome comparison was only ;2-3. This is consistent with the methylation-induced and replication-independent mechanism of CpG transitions, which constitute the majority of mutations at CpG sites. Interestingly, our study also indicated weak male mutation bias for transversions at CpG sites, implying a spontaneous mechanism largely not associated with replication. Male mutation bias was equally strong at CpG and non-CpG sites located within unmethylated ''CpG islands,'' suggesting the replication-dependent origin of these mutations. Thus, we found that the strength of male mutation bias is nonuniform in the primate genomes. Importantly, we discovered that male mutation bias depends on the proportion of CpG sites in the loci compared. This might explain the differences in the magnitude of primate male mutation bias observed among studies.

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MP79-02 Discovery of a Gene Expression Signature of Prostate Cancer Prognostication by Focusing on Indolent Tumors

The Journal of Urology, 2014

Comparative Meta-analysis of Prognostic Gene Signatures for Late-Stage Ovarian Cancer

JNCI Journal of the National Cancer Institute, 2014

Ovarian cancer is the fifth most common cause of cancer deaths in women in the United States. Num... more Ovarian cancer is the fifth most common cause of cancer deaths in women in the United States. Numerous gene signatures of patient prognosis have been proposed, but diverse data and methods make these difficult to compare or use in a clinically meaningful way. We sought to identify successful published prognostic gene signatures through systematic validation using public data.

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28-Way vertebrate alignment and conservation track in the UCSC Genome Browser

by S. Tyekucheva and D. Blankenberg

Genome Research, 2007

the power of this resource for exploring vertebrate and mammalian evolution, using three examples... more the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.

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ESPERR: Learning strong and weak signals in genomic sequence alignments to identify functional elements

Genome Research, 2006

Genomic sequence signals - such as base composition, presence of particular motifs, or evolutiona... more Genomic sequence signals - such as base composition, presence of particular motifs, or evolutionary constraint - have been used effectively to identify functional elements. However, approaches based only on specific signals known to correlate with function can be quite limiting. When training data are available, application of computational learning algorithms to multispecies alignments has the potential to capture broader and more informative sequence and evolutionary patterns that better characterize a class of elements. However, effective exploitation of patterns in multispecies alignments is impeded by the vast number of possible alignment columns and by a limited understanding of which particular strings of columns may characterize a given class. We have developed a computational method, called ESPERR (evolutionary and sequence pattern extraction through reduced representations), which uses training examples to learn encodings of multispecies alignments into reduced forms tailored for the prediction of chosen classes of functional elements. ESPERR produces a greatly improved Regulatory Potential score, which can discriminate regulatory regions from neutral sites with excellent accuracy ( approximately 94%). This score captures strong signals (GC content and conservation), as well as subtler signals (with small contributions from many different alignment patterns) that characterize the regulatory elements in our training set. ESPERR is also effective for predicting other classes of functional elements, as we show for DNaseI hypersensitive sites and highly conserved regions with developmental enhancer activity. Our software, training data, and genome-wide predictions are available from our Web site (http://www.bx.psu.edu/projects/esperr).

A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis

EMBO Molecular Medicine, 2014

5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.

curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome

by S. Tyekucheva and Ina Jazic

Database, 2013

Citation details: Ganzfried,B.F., Riester,M., Haibe-Kains,B., et al. curatedOvarianData: clinical... more

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Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease

Clinical Cancer Research, 2008

Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genom... more Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.

Cancer-Specific High-Throughput Annotation of Somatic Mutations: Computational Prediction of Driver Missense Mutations

Cancer Research, 2009

Large-scale sequencing of cancer genomes has uncovered thousands of DNA alterations, but the func... more Large-scale sequencing of cancer genomes has uncovered thousands of DNA alterations, but the functional relevance of the majority of these mutations to tumorigenesis is unknown. We have developed a computational method, called CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations), to identify and prioritize those missense mutations most likely to generate functional changes that enhance tumor cell proliferation. The method has high sensitivity and specificity when discriminating between known driver missense mutations and randomly generated missense mutations (area under ROC curve > 0.91, area under Precision-Recall curve > 0.79). CHASM substantially outperformed previously described missense mutation function prediction methods at discriminating known oncogenic mutations in TP53 and the tyrosine kinase EGFR. We applied the method to 607 missense mutations found in a recent glioblastoma multiforme sequencing (GBM) study. Based on a model that assumed the GBM mutations are a mixture of drivers and passengers, we estimate that 8% of these mutations are drivers, causally contributing to tumorigenesis.

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Human-macaque comparisons illuminate variation in neutral substitution rates

by John Karro and S. Tyekucheva

Genome Biology, 2008

Neutral substitutions in primates <p>The evolutionary distance between human and macaque is parti... more Neutral substitutions in primates <p>The evolutionary distance between human and macaque is particularly attractive for investigating neutral substitution rates, which were calculated as a function of a number of genomic parameters.</p> Abstract Background: The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the humanmacaque neutral substitution rate as a function of a number of genomic parameters.

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Stress-Related Signaling Pathways in Lethal and Non-Lethal Prostate Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 21, 2015