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Information aggregation from various gen, disease, and gen-disease databases such as DisGeNet, COSMIC, HumsaVar, Orphanet, ClinVar, HPO, and Diseases into a unique database would enable researchers to analyze and compare valuable domain findings in a more convenient and systematic way. However, the aggregation poses numerous challenges due to non-uniform information annotation across the databases. In this work, we address the problem of mapping a disease name, when needed, into a standardized disease code (DOID) based on Natural Language Processing text representation techniques. We examine the benefits and limitations of using off-the-shelf embeddings such as Med2vec, and language models such as BioBERT, UmlsBERT, and PubMedBERT in retrieval scenarios with respect to standard full-text search. In addition to qualitative improvements, we elaborate on the technical requirements and computational complexities that come with the embracement of language models and semantic search.

The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure. © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.

Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Univariate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes invo

For the last couple of decades, there has been a significant growth in sequencing data, leading to an extraordinary increase in the number of gene variants. This places a challenge on the bioinformatics research community to develop and improve computational tools for functional annotation of new variants. Genes coding for epigenetic regulators have important roles in cancer pathogenesis and mutations in these genes show great potential as clinical biomarkers, especially in hematologic malignancies. Therefore, we developed a model that specifically focuses on these genes, with an assumption that it would outperform general models in predicting the functional effects of amino acid substitutions. EpiMut is a standalone software that implements a sequence based alignment-free method. We applied a two-step approach for generating sequence based features, relying on the biophysical and biochemical indices of amino acids and the Fourier Transform as a sequence transformation method. For each gene in the dataset, the machine learning algorithm–Naïve Bayes was used for building a model for prediction of the neutral or disease-related status of variants. EpiMut outperformed state-of-the-art tools used for comparison, PolyPhen-2, SIFT and SNAP2. Additionally, EpiMut showed the highest performance on the subset of variants positioned outside conserved functional domains of analysed proteins, which represents an important group of cancer-related variants. These results imply that EpiMut can be applied as a first choice tool in research of the impact of gene variants in epigenetic regulators, especially in the light of the biomarker role in hematologic malignancies. EpiMut is freely available at https://www.vin.bg.ac.rs/180/tools/epimut.php.

Although various tools for Gene Ontology (GO) term enrichment analysis are available, there is still room for improvement. Hence, we present DiNGO, a standalone application based on an open source code from BiNGO, a widely-used application to assess the overrepresentation of GO categories. Besides facilitating GO term enrichment analyses, DiNGO has been developed to allow for convenient Human Phenotype Ontology (HPO) term overrepresentation investigation. This is an important contribution considering the increasing interest in HPO in scientific research and its potential in clinical settings. DiNGO supports gene/protein identifier conversion and an automatic updating of GO and HPO annotation resources. Finally, DiNGO can rapidly process a large amount of data due to its multithread design.DiNGO is implemented in the JAVA language, and its source code, example datasets and instructions are available on GitHub: https://github.com/radoslav180/DiNGO. A pre-compiled jar file is available at: https://www.vin.bg.ac.rs/180/tools/DiNGO.php.Supplementary data are available at Bioinformatics online.

The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the 'dark' proteome.

The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome.

Background: The significant number of protein-protein interactions (PPIs) discovered by harnessing concomitant advances in the fields of sequencing, crystallography, spectrometry and two-hybrid screening suggests astonishing prospects for remodelling drug discovery. The PPI space which includes up to 650 000 entities is a remarkable reservoir of potential therapeutic targets for every human disease. In order to allow modern drug discovery programs to leverage this, we should be able to discern complete PPI maps associated with a specific disorder and corresponding normal physiology. Objective: Here, we will review community available computational programs for predicting PPIs and web-based resources for storing experimentally annotated interactions. Methods: We compared the capacities of prediction tools: iLoops, Struck2Net, HOMCOS, COTH, PrePPI, InterPreTS and PRISM to predict recently discovered protein interactions. Results: We described sequence-based and structure-based PPI prediction tools and addressed their peculiarities. Additionally, since the usefulness of prediction algorithms critically depends on the quality and quantity of the experimental data they are built on; we extensively discussed community resources for protein interactions. We focused on the active and recently updated primary and secondary PPI databases, repositories specialized to the subject or species, as well as databases that include both experimental and predicted PPIs. Conclusion: PPI complexes are the basis of important physiological processes and therefore, possible targets for cell-penetrating ligands. Reliable computational PPI predictions can speed up new target discoveries through prioritization of therapeutically relevant protein–protein complexes for experimental studies.

Methylation of p16 and p14 genes is a common event in colorectal cancers; however, their exact role in the prediction of patients' outcome is unclear. We conducted this retrospective study to evaluate their potential predictive and/or prognostic roles. Methylation-specific PCR was used to examine the methylation status of p16 and p14 in pretherapeutic and preoperative biopsy specimens of 60 patients with locally advanced rectal cancer. The methylation status of the examined genes did not affect the response to preoperative chemoradiotherapy (CRT), recurrence rate and overall survival. However, patients with a simultaneous presence of either p16 or p14 methylation and high vascular endothelial growth factor (VEGF) expression showed a significantly worse response to CRT (p=0.005 and p=0.038, respectively). Moreover, patients with both p16 methylation and high VEGF expression had significantly shorter overall survival (p=0.010), while no such association was found in patients with p14 methylation and high VEGF expression. On the other hand, a subgroup of patients with p16 methylation and low VEGF and high epidermal growth factor receptor (EGFR) expression showed a significantly better response to CRT (p=0.024). The obtained results point to the importance of p16 and p14 methylation analyses in combination with VEGF and EGFR expression, aimed at better predicting treatment response and patient outcome. © 2018 by the Serbian Biological Society.

Breast cancer (BC) is a heterogeneous disease in an urgent need for developing novel research, classification, and therapy approaches. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) proteins are well described tumor suppressors with great potential to be the subjects of different therapies. MicroRNAs (miRNAs) are genetic elements that might be used to solve the complex BC puzzle. BRCA1 was described to be the target of up to 100 miRNAs. BRCA1 may directly repress miR-155 activity. In addition, miR-15/107/182-mediated downregulation of BRCA1 interrupt DNA repair and may change the course of BC therapy. miR-146a and miR-146-5p silencing BRCA1 may trigger formation of triple-negative and basal-like sporadic BC cases. miR-182 might effect the therapy outcome. miR-21 targeted therapy might be useful for the treatment of BRCA2 mutation carriers. miR-342 overexpression and the absence of functional BRCA1 gene might cause synthetic lethality, which might be used as a base for future therapies. The present review discusses the latest data from studies that focus on the complex network of miRNAs and BRCA1/2 related BCs, which might be important for improving the therapy within the patients with triple-negative BC (TNBC) and basal-like BC, and for understanding the formation of TNBC.

Background: Preoperative chemoradiotherapy (CRT) represents the standard treatment for patients with locally advanced rectal cancer. Since only subset of patients has benefit from this preoperative treatment, development of reliable molecular biomarkers is required. In this retrospective study, we investigated methylation status of p16 and p14 tumor suppressor genes in locally advanced rectal cancer, in order to evaluate their potential predictive and prognostic role. Methods: Methylation-specific PCR was used to examine methylation status of p16 and p14 genes in pretherapeutic and preoperative biopsy specimens of 60 patients with locally advanced rectal cancer. Results: Aberrant methylation of p16 and p14 genes was detected in 43.3% (26/60) and 39.6% (23/58) of cases, respectively. In general, p16 and p14 methylation status did not affect the response to CRT, recurrences rate and overall survival. However, patients with simultaneous presence of either p16 or p14 methylation and high vascular endothelial growth factor (VEGF) expression showed significantly worse response to CRT (p = 0.005 and p = 0.038, respectively). In addition, tendency toward more frequent local recurrences and metastasis was observed in cases with concurrent presence of methylation of either p16 or p14 gene and high VEGF expression (p = 0.075 and p = 0.072, respectively), while patients with both of p16 methylation and high VEGF expression had significantly shorter overall survival (p = 0.010). Conclusion: Obtained results strongly suggest the importance of p16 and p14 methylation analyses in combination with other parameters, particularly VEGF expression, in order to better predict treatment response and patient outcome.

To determine various clinical, radiographic, and pathological parameters which may indicate an increased risk of Giant cell tumour of bone (GCTB) recurrence after surgical therapy. The study included a total of 164 GCTB samples; 118 (72 %) primary tumours, and 46 (28 %) recurrences; which were analyzed on immunohistochemistry for expression of Ki67, p53, cyclin D1, and beta-catenin. Among 13 analyzed clinical, radiological, and histological variables, which presented possible predictive factors for the incidence of GCTB relapse, univariate logistic regression (ULR) extract three highly statistically significant parameters: 1) lesion localization, 2) nuclear p53 expression in mononuclear cells, and 3) nuclear cyclin D1 expression in giant multinuclear cells. The multivariate logistic regression (MLR), revealing that p53 expression in mononuclear cells was the most significant predictive factor (HR = 6,181 p LT 0,001), the positivity of which indicated six times higher probability for recurrence in GCTB. The expression of cyclin D1 in giant cells, containing less than 15 nuclei, was also statistically significant (HR = 8,398, p = 0,038) for predicting the recurrence, and demonstrated eight times more frequent recurrence in positive tumours. This study confirmed independent predicting factors for GCTB reccurence: p53 expression in mononuclear tumour cells and cyclin D1 expression in giant multinuclear cells. Results are new addition to generally known parameters, such as: localization of lesion, number of surgical interventions, clear destruction of cortex with the presence of extracompartmental lesion, and histological criteria for malignancy and can help in further research and treatment of GCTB.

Breast cancer (BC) is a heterogeneous group of diseases that still represents a major cause of death in the female population. MicroRNAs (miRNAs, miRs), such as miR-221 and miR-222, have been shown to be involved in BC pathology by acting via its target genes such as tissue inhibitor of metalloproteinase 3 (TIMP3). The main goals of this study were to find differences in miR-221/222 levels of expression in BC groups based on invasiveness, and to investigate the association with estrogen receptor (ER), TIMP3 messenger RNA (mRNA) levels, and clinicopathological characteristics of patients and tumors. In this study, we measured levels of miR-221/222 in 63 breast tissue samples by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using TaqMan(A (R)) technology and immunohistochemistry. miR-221/222 levels varied significantly across groups based on invasiveness (P LT 0.001). In in situ tumors, miR-221 and miR-222 were negatively associated with ER (P = 0.001, r = -0.714, and P = 0.013, r = -0.585, respectively). In invasive breast carcinomas associated with non-invasive tumors, miR-222 was inversely associated with ER (P = 0.039, r = -0.620). Pure invasive BCs showed a positive correlation of miR-221 and miR-222 with TIMP3 mRNA levels (P = 0.008, r = 0.508, and P = 0.010, r = 0.497, respectively). An increase in miR-221/222 might be an important event for in situ carcinoma formation, and miR-221/222 may be important molecules that highlight potential differences between invasive breast carcinomas associated with non-invasive and pure invasive BCs.

Aim of the study is to determine the possible roles of p53, cyclin D1, B-catenin and Ki-67 in the increase in risk of fractures in patients with giant cell tumor of bone. The study included a total of 164 patients with giant cell tumor of bone (GCTB), 21 (12.8%) with and 143 (87.2%) without fracture. The samples were analyzed immunohistochemically for expression of Ki-67, p53, cyclin D1 and beta-catenin. According to the immunohistochemical expression of p53 and Ki-67 in mononuclear stromal cells, as well as of cyclin D1 in multinuclear giant cells, there was no significant association with immunopositivity and risk of fractures. However, our research revealed that patients with cytoplasmic expression of beta-catenin in stromal cells had three times more frequent occurrence of pathological fractures, which was highly statistically significant (chi(2) = 7.065; p = 0.008). Moreover, a highly statistically significant correlation between the nuclear expression of beta-catenin in giant cells and the incidence of pathological fractures was also found (chi(2) = 8.824; p = 0.003). The study showed that beta-catenin expression highly correlates with the incidence of pathological fractures in patients with GCTB. Taking into account that beta-catenin is closely linked to activation of the Wnt signaling pathway in GCTB pathogenesis, one could postulate that activation of the Wnt pathway is one of the contributing factors to locally destructive behavior of this tumor, as well as to the incidence of pathological fractures.

X-chromosome instability has been a long established feature in Alzheimer's disease ( AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, "Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes ofwomen affected by AD?" To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes ofwomen with AD. Our results showed skewed inactivation patterns (>90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women.

Rhabdomyosarcoma (RMS) is a highly malignant cancer. Over the last two decades, prognosis for RMS patients has significantly improved, with the exception of those in the high-risk group. In order to identify new prognostic factors, we investigated the expression of nestin in RMS cells and its correlation with clinicopathological features and patient outcome. The analysis of overall survival for all patients (N = 30) revealed 1-, 2-, 3-, 4-, and 5-year survival rates of 93.3, 83.3, 66.7, 63.3, and 63.3%, respectively. Nestin overexpression significantly correlated with survival (P = 0.044). Survival of patients with = 50% nestin-positive cells was 90, 70, and 40% after 1, 2, and 3 years, respectively, and remained unchanged until the end of the investigation period. The study group composed of patients exhibiting nestin expression in GT 50% of cells showed 1-, 2-, 3-, and 4-year survival rates of 95, 90, 80, and 75%, respectively, remaining stable at 75% for the fifth year of observation. A nestin-positive expression rate lower than 50% was observed more frequently in older patients (43.60 +/- 27.58 years; P = 0.028). In addition, higher rates of nestin expression were observed in most embryonal RMS specimens and low-grade tumors, in early stages of the disease, and among younger patients. Our results lead us to propose nestin as possible positive prognostic factor in RMS.

X-chromosome instability has been a long established feature in Alzheimers disease ( AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes ofwomen affected by AD? To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes ofwomen with AD. Our results showed skewed inactivation patterns ( GT 90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women.

Липосаркоми, тумори мезенхималног порекла, представљају најучесталијихистолошки тип саркома меких ткива. Групу карактерише велика разноликосткако у погледу патохистолошке организације тумора тако и биологије понашања.Уобичајена подела липосаркома обухвата следећа три подтипа: а.) добродиферентовани / дедиферентовани, б.) миксоидни / округлоћелијски и в.)плеоморфни. С обзиром на значајне клиничко-патолошке разлике између триподтипа липосаркома, вероватно је да су различити механизми укључени у њиховнастанак и развој. На основу студија које су се фокусирале на истраживањегенетике саркома меких ткива и костију, може се закључити да сигнални путевиp53-p14 и Rb-p16 играју одређену улогу у свим типовима саркома. Разјашњавањеулоге ових сигналних путева у патогенези липосаркома, може да буде доприноскако дијагностици и прогностици липосаркома, тако и дефинисању потенцијалнихтерапеутских циљева. Студија је обухватила испитивање мутационог статуса генар53 и метилационог статуса гена р14 и р16, на 33 узорка липосаркома, сва триподтипа. У циљу свеобухватније анализе испитивана је и експресија протеина р16,циклина D1 и фактора пролиферације Ki-67, применом имунохистохемијскогбојења. Резултати експеримента су показали да промене у сигналним путевимар53-р14 и р16-Rb могу имати значаја у патогенези сва три подтипа липосаркома.Разлике се огледају у квалитету и квантитету промена., Liposarcoma, tumors of mesenchymal origin, represent the most frequent type ofsoft tissue sarcomas. The group is characterized by a great diversity regardingpathohistology and biological behavior. The group can be divided into three differentsubtypes: a.) well differentiated / dedifferentiated, b.) myxoid / round cell and c.)pleomorphic. Given the significant clinical and pathological differences between thethree subtypes of liposarcoma, it is likely that different mechanisms are involved in theirformation and development. Based on the studies that have been focused on geneticresearch of sarcoma of soft tissues and bones, conclusion can be drawn that the p53-p14and Rb-p16 signaling pathways play a certain role in sarcomagenesis. Clarification ofthe role of these signaling pathways in the pathogenesis of liposarcoma, could be acontribution towards better diagnostic and prognostic criteria and the identification ofpotential therapeutic targets. The study included examination of the p53 gene mutationstatus and assessment of the p14/p16 gene methylation status in 33 liposarcoma samplesof all three subtypes. For the purpose of more comprehensive analysis, proteinexpression of the p16, cyclin D1 and Ki-67 has been evaluated byimmunohistochemical staining. The results of the study have showed that the alterationsof the targeted signal pathways are important in the pathogenesis of all three subtypes ofliposarcoma. The differences are reflected in the quality and quantity of the detected alterations.

Methylation-specific PCR (MSP) is still the method of choice for a single gene methylation study. The proper design of the primer pairs is a prerequisite for obtaining reliable PCR results. Despite numerous protocols describing the rules for MSP primer design, none of them provide a comprehensive approach to the problem. Our aim was to depict a workflow for the primer design that is concise and easy to follow. In order to achieve this goal, adequate tools for promoter sequence retrieval, MSP primer design and subsequent in silico analysis are presented and discussed. Furthermore, a few instructive examples regarding a good versus a poor primer design are provided. Finally, primer design is demonstrated according to the proposed workflow. This article aims to provide researchers, interested in a single gene methylation studies, with useful information regarding successful primer design.

Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16(INK4a)/p14(ARF) genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14(ARF) gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14(ARF) promoter. The results from the current study suggest significant impact of the p14(ARF) gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma.

In this study, methylation-specific polymerase chain reaction was used to investigate the role and potential prognostic significance of the methylation status of p16, p15, MGMT and DAPK genes in 32 specimens of follicular lymphoma (FL). Hypermethylation of p15 gene was associated with lower hemoglobin level (P = 0.020) and MGMT/DAPK comethylation with relapsed disease (P = 0.018). Among all patients with FL, there was no significant difference in the overall survival between those with hypermethylated and unmethylated of any examined genes. Therefore, we analyzed methylation in the different groups according to FL International Prognostic Index (FLIPI) and tumor grade. In the high-risk group, patients with hypermethylated p16 gene had significant lower overall survival than those with unmethylated p16 (P = 0.006) and trend toward shorter failure-free survival (P = 0.068). In the same risk group, there was a trend toward longer overall survival for patients with hypermethylated MGMT gene, compared to those with unmethylated MGMT gene (P = 0.066). p15 methylation had impact on shorter overall survival in grade I group of patients (P = 0.013), and DAPK methylation tended to have impact on shorter failure-free survival in the whole examined group (P = 0.079). Our results suggest that promotermethylation of p16 and MGMT genes could have prognostic value when used in combination with the FLIPI and p15 methylation in combination with tumor grade. Concurrent methylation of MGMT and DAPK genes could be the marker of tumor chemoresistance and disease recurrence.

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen.