scholarly journals DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features

2020 ◽  
Vol 6 (46) ◽  
pp. eaba6784
Author(s):  
Jie Lyu ◽  
Jingyi Jessica Li ◽  
Jianzhong Su ◽  
Fanglue Peng ◽  
Yiling Elaine Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Gene Networks ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Cancer Driver ◽  
Dual Functional ◽  
Cancer Driver Genes

Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.

scholarly journals DORGE: Discovery of Oncogenes and Tumor SuppressoR Genes Using Genetic and Epigenetic Features

2020 ◽  
Author(s):  
Jie Lyu ◽  
Jingyi Jessica Li ◽  
Jianzhong Su ◽  
Fanglue Peng ◽  
Yiling Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Gene Networks ◽  
Genetic Alterations ◽  
Prediction Algorithm ◽  
Missense Mutations ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Cancer Driver ◽  
Cancer Driver Genes

AbstractComprehensive data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important contributors to tumor initiation and progression, most known driver genes were identified based on genetic alterations alone, and it remains unclear to what the extent epigenetic features would facilitate the identification and characterization of cancer driver genes. Here we developed a prediction algorithm DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), which integrates the most comprehensive collection of tumor genetic and epigenetic data to identify TSGs and OGs, particularly those with rare mutations. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancer percentages, and methylation differences between cancer and normal samples as strong predictors for OGs. We extensively validated novel cancer driver genes predicted by DORGE using independent functional genomics data. We also found that the dual-functional genes, which are both TSGs and OGs predicted by DORGE, are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed a previously undetected repertoire of cancer driver genes.

scholarly journals Somatic Selection Distinguishes Oncogenes and Tumor Suppressor Genes

2019 ◽  
Author(s):  
Pramod Chandrashekar ◽  
Navid Ahmadinejad ◽  
Junwen Wang ◽  
Aleksandar Sekulic ◽  
Jan B Egan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Tumor Biology ◽  
Supplementary Information ◽  
Cancer Type ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Cancer Driver ◽  
Cancer Driver Genes ◽  
Somatic Selection

Abstract Motivation Functions of cancer driver genes vary substantially across tissues and organs. Distinguishing passenger genes (PGs), oncogenes (OGs) and tumor suppressor genes (TSGs) for each cancer type is critical for understanding tumor biology and identifying clinically actionable targets. Although many computational tools are available to predict putative cancer driver genes, resources for context-aware classifications of OGs and TSGs are limited. Results We show that the direction and magnitude of somatic selection of protein-coding mutations are significantly different for PGs, OGs and TSGs. Based on these patterns, we develop a new method (genes under selection in tumors, GUST) to discover OGs and TSGs in a cancer-type specific manner. GUST shows a high accuracy (92%) when evaluated via strict cross-validations. Its application to 10,172 tumor exomes found known and novel cancer drivers with high tissue-specificities. In 11 out of 13 OGs shared among multiple cancer types, we found functional domains selectively engaged in different cancers, suggesting differences in disease mechanisms. Availability An R implementation of the GUST algorithm is available at https://github.com/liliulab/gust. A database with pre-computed results is available at https://liliulab.shinyapps.io/gust. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Blood ◽  
2016 ◽  
Vol 128 (13) ◽  
pp. 1735-1744 ◽  
Author(s):  
Niels Weinhold ◽  
Cody Ashby ◽  
Leo Rasche ◽  
Shweta S. Chavan ◽  
Caleb Stein ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Clonal Selection ◽  
Therapeutic Approaches ◽  
Apoptosis Resistance ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Key Points

Key PointsHits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate–driving relapse. Excessive biallelic inactivation of tumor suppressors in high-risk cases highlights the need for TP53-independent therapeutic approaches.

Aberrant Gene Promoter Methylation of Tumor Suppressor Genes in Plasma Cell Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2487-2487
Author(s):  
Carmen Stanganelli ◽  
Jorge Arbelbide ◽  
Juliana Zimerman ◽  
Dorotea Beatriz Fantl ◽  
Claudia Corrado ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Peripheral Blood ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Genetic Alterations ◽  
Negative Regulator ◽  
Epigenetic Mechanism ◽  
Gene Methylation ◽  
Suppressor Genes ◽  
Number Of Genes

Abstract There is increasing evidence that, in addition to genetic aberrations, epigenetic processes play a major role in carcinogenesis. Particularly, hypermethylation of CpG islands of the promoter regions of tumor suppressor genes (TSG) is now considered as an important epigenetic mechanism for gene inactivation. Multiple myeloma (MM) is characterized by neoplastic proliferation of monoclonal plasma cells. The natural course of disease may progress through monoclonal gammopathy of undetermined significance (MGUS) to MM. During this process, multiple genetic alterations are sequentially acquired and aberrant promoter hypermethylation might be one of the steps involved in this progression. In this study, we have evaluated methylation status of the following TSG: p15INK4b, p16INK4a, p14ARF, SOCS-1, p27KIP1, RASSF1A and p73 genes, in order to determine if they were involved in the evolution of MGUS to MM. Forty four MM (21 males; mean age 67.5 years; Durie-Salmon clinical stages: I: 20%, II:14% and III: 66%) and 21 MGUS patients (6 males; mean age 68 years) were study. All patients gave informed consent and the study was approved by the Ethics Committee of our Institution. Peripheral blood samples from 10 normal individuals and CpGenome Universal Methylated DNA (Chemicon International) were used as negative and positive controls, respectively. DNA was extracted from bone marrow cells of patients and peripheral blood lymphocytes of controls using phenol/chloroform method. Methylation status was performed using Methylation Specific PCR (MSP) technique. For statistical analysis, Student t and Fisher exact tests were used. The methylation index (MI; ratio between the number of genes methylated and the number of genes analyzed) was also calculated. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS patients (14%) (p=0,006). Frequencies of methylation of p14ARF, p15INK4b, p16INK4a and RASSF1A were comparable in both entities: 29%, 32%, 7% and 2%, respectively, for MM; and 29%, 29%, 5% and 0%, respectively, for MGUS. TP73 gene showed a tendency of higher methylation in MM (45%) than in MGUS (33%). All patients lacked methylation at p27KIP1 gene. Whereas the percentage of MM with at least one gene methylated (84%) did not showed differences to that of MGUS (66%), the mean MI of MGUS was lower (0.16; range 0.14-0.43) than that of MM (0.24; range 0.14-0.71) (p<0.05). None of the target genes were methylated in normal samples. No statistical significant correlation with clinical characteristics: gender, age, isotype, level of M-component, type of light chain, stage of the disease, haemoglobin, serum albumin level, calcium, β2 microglobulin and LDH, were observed. To our knowledge, this is the first report of methylation in MM and MGUS from Argentina. The similar frequency of p14ARF, p15INK4b, p16INK4a and RASSF1A gene methylation observed in MM and MGUS would suggest that they are probably not involved in the progression of MGUS. However, SOCS1 gene methylation was significantly more frequent in MM than in MGUS suggesting that methylation of this gene might be involved in clonal evolution of MGUS to MM. SOCS1 is a negative regulator of cytokine signaling, being important in normal lymphocyte development and differentiation. Silencing of SOCS1 may result in greater responsiveness to cytokines, which may favour the neoplastic development.

scholarly journals Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 850 ◽  
Author(s):  
Mohammed I. Y. Elmallah ◽  
Olivier Micheau
Keyword(s):  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Tumor Suppressor Genes ◽  
Histone Deacetylase Inhibitors ◽  
Tumor Regression ◽  
Genetic Alterations ◽  
Cancer Etiology ◽  
Suppressor Genes ◽  
Histone Proteins ◽  
Wide Range

One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation. For example, HATs are a group of enzymes, which are responsible for the acetylation of histone proteins, resulting in chromatin relaxation and transcriptional activation, whereas HDACs by deacetylating histones lead to chromatin compaction and the subsequent transcriptional repression of tumor suppressor genes. Direct acetylation of suppressor genes or oncogenes can affect their stability or function. Histone deacetylase inhibitors (HDACi) have thus been developed as a promising therapeutic target in oncology. While these inhibitors display anticancer properties in preclinical models, and despite the fact that some of them have been approved by the FDA, HDACi still have limited therapeutic efficacy in clinical terms. Nonetheless, combined with a wide range of structurally and functionally diverse chemical compounds or immune therapies, HDACi have been reported to work in synergy to induce tumor regression. In this review, the role of HDACs in cancer etiology and recent advances in the development of HDACi will be presented and put into perspective as potential drugs synergizing with TRAIL’s pro-apoptotic potential.

Current Understanding of Epigenetics Driven Therapeutic Strategies in Colorectal Cancer Management

2021 ◽  
Vol 21 ◽  
Author(s):  
Dikshita Deka ◽  
Marco Scarpa ◽  
Alakesh Das ◽  
Surajit Pathak ◽  
Antara Banerjee
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Tumor Suppressor Genes ◽  
Genetic Alterations ◽  
Primary Role ◽  
Suppressor Genes ◽  
Cancer Management ◽  
Cancer Pathogenesis

: Colorectal cancer is known to be the paramount reason for cancer deaths around the globe. It occurs due to the aggregation of epigenetic and genetic alterations in colon epithelial cells that transmute them into adenocarcinomas. Epigenetic mechanisms are interpreted as the changes in expression of the gene which is not associated with the alterations in the principal DNA sequence, while genetic changes involve modifications in oncogenes and tumor suppressor genes. The changes in the epigenetic in colon cancer that transmute colonic epithelial cells include chromatin modifications, microRNA expression, telomere length, and DNA methylation. DNA hypermethylation causes down-regulation and unsuitable expression of specific microRNA which can behave like tumor suppressor genes. Histone modifications can also influence the chromatin remodeling and the gene expression, hence performs an eminent function in silencing of the gene in colon cancer. Moreover, the telomere/telomerase interaction is a prime mechanism to embrace both cellular replicative potential and genomic instability and its malfunction plays a primary role in colon cancer. Deducing the genesis and the function of epigenetic abnormality in colon cancer pathogenesis will head to a potent prevention and therapeutic approach for colon cancer patients. Epigenetic drugs which emphasizes the convertible essence of epigenetic occurrences have accompanied the probability of epigenetic approach as a treatment alternative in colon cancer. Hence, this review is undertaken to critically envelop the recent advance events in colorectal cancer therapies with a special emphasis on remedies targeting epigenetic modulators and future challenges towards therapeutic interventions.

scholarly journals Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 749
Author(s):  
Agnieszka Koppolu ◽  
Radosław B. Maksym ◽  
Wiktor Paskal ◽  
Marcin Machnicki ◽  
Beata Rak ◽  
...  
Keyword(s):  
Uterine Cavity ◽  
Genetic Alterations ◽  
Deep Infiltrating Endometriosis ◽  
Driver Genes ◽  
Kras Mutations ◽  
Deep Endometriosis ◽  
Eutopic Endometrium ◽  
Cancer Driver ◽  
Cancer Driver Genes ◽  
Custom Panel

Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

scholarly journals The Evolution of Human Cancer Gene Duplications across Mammals

2020 ◽  
Author(s):  
Marc Tollis ◽  
Aika K. Schneider-Utaka ◽  
Carlo C. Maley
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Cancer Gene ◽  
Suppressor Genes ◽  
Copy Numbers

AbstractCancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species’ cancer gene copy number and it’s longevity, but not body size, contrary to predictions from Peto’s Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

Genetic Alterations in Microsatellite Marker Sites among Tumor Suppressor Genes in Endometriosis

2001 ◽  
Vol 51 (4) ◽  
pp. 240-242 ◽  
Author(s):  
Kuniaki Nakayama ◽  
Toshihiko Toki ◽  
Toshio Nikaido ◽  
Ya-Li Zhai ◽  
Ikuo Konishi
Keyword(s):  
Tumor Suppressor ◽  
Microsatellite Marker ◽  
Tumor Suppressor Genes ◽  
Genetic Alterations ◽  
Suppressor Genes

Distinct Patterns of Genomic Alterations in Adult T-Cell Leukemia-Lymphoma Endemic in the Western World

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1698-1698
Author(s):  
Agustin Pimentel ◽  
Andrea O'Hara ◽  
Rosangela de Lima ◽  
Suying Xu ◽  
Ngoc Toomey ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Copy Number ◽  
Genetic Alterations ◽  
Western World ◽  
Acute Type ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Suppressor Genes

Abstract Introduction: Acute T-cell leukemia/lymphoma (ATLL) is a highly aggressive malignancy caused by HTLV-I, which is endemic in Japan, the Caribbean, and South America. ATLL carries a dismal prognosis and is generally incurable with conventional chemotherapy. ATLL is challenging to study at the molecular level, in part due to its complex genetic alterations likely resulting from years of HTLV-I driven T-cell proliferation and accumulation of genetic damage prior to malignant transformation. While no specific chromosome or genetic abnormalities have been proven to contribute to the pathogenesis of ATLL, older comparative genomic hybridization (CGH) studies performed in Japanese patients have demonstrated frequent genetic lesions (gains and losses) involving specific chromosomal regions, thus limited information exists about the chromosomal abnormalities occurring in the African ATLL variant commonly seen in the Western World. Methods: In this study, we used a high-density oligo array 244K platform CGH platform (Agilent Technologies) with an average resolution of 8.9 Kb, to perform a comprehensive genomic analysis of 47 ATLL patient tumor specimens obtained from African-descendants in the United States, Caribbean and Brazil. Patients were sub-classified as acute-type (A) ATLL (n=31), lymphomatous (L) (n=8), chronic (n=7, six whom had unfavorable features), and one with smouldering type according to Shimoyama criteria. DNA samples were extracted from peripheral blood mononuclear cells or tumor samples from these patients and checked for quality. Results: ATLL tumors exhibited complex genomic abnormalities and high copy number changes (CNCs). The average of copy number (CN) aberrations per sample was 238 in the L-group vs. 114 in acute/unfavorable chronic (A/UC) group. However, many chromosomal alterations were observed in this cohort, which had not been previously reported by other studies. The common CNCs were gains at 1q21-q44, 3, 3p, 7q22-q36, 8, 18, 19p13.1-p13.3, 21q21.1-q22.3, 22q12-q13 and losses at 5q13.2-q32, 6q11-q15, 9q13-q21. Gains in the 14 q32 (IGH) regions and losses in the 7p14.1 (TCRG), 7q34 (TCRB) and 14q11.2 (TCRA) regions involving small DNA segments were frequently observed. Genomic losses involving at least one or more known or candidate tumor suppressor genes were found in nearly all tumors, including some genes not previously implicated in ATLL. Some of the most significant gene or locus specific losses occurring in at least 20 % of the tumors in aggressive ATLL subtypes (A/UC and L) are summarized in Table 1. Losses of CDKN2A and CDKN2B tumor suppressor genes have been previously implicated in ATLL and other cancers. Several other genes found by this analysis have been implicated in apoptosis or cancer (i.e. CBLB, ANKRD11, IKZF1, and EPC1). IMMP2L deletion was associated with shorter survival time (2.3 weeks) compared with those cases without this gene deletion (29 weeks) in the A/UC group (p=0.005). ANKRD11 homo- or heterozygous deletions were seen in 37% of L-type and 19% of acute-type cases, and were associated with a shorter survival (13 vs. 43 weeks, p=<0.05) in the A group. CPN2/LRRC15 locus gains in 32% of A-type were linked to poorer survival (16 vs. 42 weeks, p=0.05). Table 1. GENE FUNCTION LOSSES (n) GAINS (n) NRXN3 Membrane receptor, cell adhesion 23 A/UC 3 L NS IMMP2L Mitochondrial inner membrane peptidase 16 A/UC* 5 L 4 A/UC CDKN2A/ CDKN2B (P16INK4/p15INK4b) Cyclin-dependent kinase inhibitors, tumor suppressors 16 A/UC 2 L 1 A/UC 1 L CBLB E3 ubiquitin protein ligase 12 A/UC 1 L NS ANKRD11 Transcriptional inhibitor, co-activator of p53 6 A/UC* 3 L NS CPN2 Carboxypeptidase NS 10 A/UC* 2 L IKZF1 Zinc-finger DNA binding proteins , lymphocyte differentiation NS 6 A/UC 3 L INSIG1 Endoplasmic reticulum membrane protein, intracellular lipid metabolism NS 10 A/UC 1 L EPC1 Member of the polycomb group family, transcriptional activator and repressor 10 A/UC 2 L NS * are genomic imbalances associated with a statistically significant reduction in survival. NS: non-significant. Conclusion: In sum, using a high resolution CGH array we observed distinct patterns ofgenetic aberrations in ATLL endemic in the Western World. We have successfully narrowed the genomic regions containing potential candidate genes that could be relevant to the pathogenesis of this fatal disease. Functional studies are required to determine the role of some of these genes in the pathogenesis of ATLL. Disclosures O'Hara: BioDiscovery, Inc.: Employment.

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