scholarly journals OncoSimulR: genetic simulation of cancer progression with arbitrary epistasis and mutator genes

2016 ◽  
Author(s):  
Ramon Diaz-Uriarte
Keyword(s):  
Cancer Progression ◽  
Genetic Interactions ◽  
Mutation Rates ◽  
Order Effects ◽  
Special Focus ◽  
Link Type ◽  
Asexual Populations ◽  
Genetic Simulation ◽  
Parent Child Relationships ◽  
Mutator Genes

AbstractOncoSimulR implements forward-in-time genetic simulations of diallelic loci in asexual populations with special focus on cancer progression. Fitness can be defined as an arbitrary function of genetic interactions between multiple genes or modules of genes, including epistasis, restrictions in the order of accumulation of mutations, and order effects. Mutation rates can be made to differ between genes, and can be affected by (anti)mutator genes. Also available are sampling from single or multiple simulations, including single-cell sampling, plotting the parent-child relationships of the clones and generating and plotting random fitness landscapes.Availability and implementationImplemented in R and C++, freely available from BioConductor for Linux, Mac, and Windows under the GNU GPL license. Version 2.3.12 or higher available from: http://www.bioconductor.org/packages/devel/bioc/html/OncoSimulR.html. GitHub repository at: https://github.com/rdiaz02/OncoSimul.

Kinase Phosphorylation-based Mechanisms of PARP Inhibitor Resistance During Synthetic Lethal Oncotherapy

2020 ◽  
Vol 15 (1) ◽  
pp. 12-23
Author(s):  
Eriko Osaki ◽  
Shinya Mizuno
Keyword(s):  
Cancer Progression ◽  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Clinical Importance ◽  
Parp Inhibition ◽  
Special Focus ◽  
Driver Genes ◽  
Kinase Phosphorylation

Background: Poly-(ADP-Ribose) Polymerase (PARP) plays a central role in recovery from single-strand DNA (ssDNA) damage via base excision repair. When PARP activity is inhibited by a NAD+ mimetic analog, ssDNA is converted into a Double-Strand Break (DSB) during the S-phase in a cell cycle. However, the DSB site is repaired in a process of Homologous Recombination (HR) that is derived by genes such as BRCA1/2, PALB2, and RAD51. Under conditions of HR dysfunction, including mutations of BRCA1/2 (called BRCAness), PARP inhibitor (PARPi) induces “synthetic lethality” in BRCAness-specific cancer cells. Indeed, clinical trials using forms of PARPi that include olaparib, veliparib and rucaparib, have revealed that PARP inhibition produces a dramatic effect that actually arrests cancer progression. Its clinical efficiency is limited, however, due to the acquisition of PARPi resistance during long-term use of this inhibitor. Thus, it is important to elucidate the mechanisms of PARPi resistance. Methods: We searched the scientific literature published in PubMed, with a special focus on kinase phosphorylation that is involved in acquiring PARPi resistance. We also summarized the possible molecular events for recovering HR system, a key event for acquiring PARPi resistance. Results: CDK1 is a critical kinase for 5’-3’ DNA end resection, which is important for generating ssDNA for recruiting HR-priming factors. CDK12 is necessary for the transcription of HR-driver genes, such as BRCA1, BRCA2, RAD51 and ATR via the phosphorylation of RNA Pol-II. PLK-1 participates in driving HR via the phosphorylation of RAD51. The PI3K-AKT-mTOR signaling cascade is involved in BRCA1 induction via an ETS1 transcriptional pathway. Even under ATMdeficient conditions, the ATR-CHK1 axis compensates for loss in the DNA damage response, which results in HR recovery. The HGF receptor Met tyrosine kinase is responsible for promoting DNA repair by activating the PARP catalytic domain. Conclusion: These kinase-based signaling pathways are biologically important for understanding the compensatory system of HR, whereas inactivation of these kinases has shown promise for the release of PARPi resistance. Several lines of preclinical studies have demonstrated the potential use of kinase inhibitors to enhance PARPi sensitivity. We emphasize the clinical importance of chemical inhibitors as adjuvant drugs to block critical kinase activities and prevent the possible PARPi resistance.

scholarly journals LOXL2 Inhibitors and Breast Cancer Progression

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 312
Author(s):  
Sandra Ferreira ◽  
Nuno Saraiva ◽  
Patrícia Rijo ◽  
Ana S. Fernandes
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Breast Cancer Cells ◽  
Lysyl Oxidase ◽  
Breast Cancer Progression ◽  
Special Focus ◽  
Amine Oxidases ◽  
Cross Link ◽  
Promising Strategy

LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment.

scholarly journals Identity and compatibility of reference genome resources

2021 ◽  
Author(s):  
Michał Stolarczyk ◽  
Bingjie Xue ◽  
Nathan C. Sheffield
Keyword(s):  
Coordinate System ◽  
Genome Analysis ◽  
Reference Genome ◽  
Reference Data ◽  
Coordinate Systems ◽  
Link Type ◽  
Novel Approach ◽  
Many Sources ◽  
Parent Child Relationships ◽  
Parent Child

Genome analysis relies on reference data like sequences, feature annotations, and aligner indexes. These data can be found in many versions from many sources, making it challenging to identify and assess compatibility among them. For example, how can you determine which indexes are derived from identical raw sequence files, or which annotations share a compatible coordinate system? Here, we describe a novel approach to establish identity and compatibility of reference genome resources. We approach this with three advances: First, we derive unique identifiers for each resource; second, we record parent-child relationships among resources; and third, we describe recursive identifiers that determine identity as well as compatibility of coordinate systems and sequence names. These advances facilitate portability, reproducibility, and re-use of genome reference data.Availabilityhttps://refgenie.databio.org

The evolution of mutation rates via DNA base composition and mutator genes: A proposition

1976 ◽  
Vol 59 (2) ◽  
pp. 353-360 ◽  
Author(s):  
Wolfgang Presber ◽  
Cornelia Schroeder ◽  
Detlev H. Krueger
Keyword(s):  
Base Composition ◽  
Mutation Rates ◽  
Dna Base Composition ◽  
Dna Base ◽  
Mutator Genes

Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 418-418
Author(s):  
Jingyuan Wang ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
Richard M. Goldberg ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Dna Damage Repair ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Mutation Rates ◽  
Aberrant Expression ◽  
Damage Repair

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p < .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p < .05). Significantly higher prevalence of TMB-high ( > 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p < .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p < .01)and RELA (29% vs 0%, p < .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.

scholarly journals Interplay of Driver, Mini-Driver, and Deleterious Passenger Mutations on Cancer Progression

2016 ◽  
Author(s):  
Xin Li ◽  
D. Thirumalai
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Evolutionary Model ◽  
Mutation Rates ◽  
Fitness Advantage ◽  
Dissipative Dynamical Systems ◽  
Passenger Mutations ◽  
The Relationship ◽  
Surprising Finding ◽  
Stochastic Evolutionary Model

Cancer is caused by the accumulation of a critical number of somatic mutations (drivers) that offer fitness advantage to tumor cells. Moderately deleterious passengers, suppressing cancer progression, and mini-drivers, mildly beneficial to tumors, can profoundly alter the cancer evolutionary landscape. This observation prompted us to develop a stochastic evolutionary model intended to probe the interplay of drivers, mini-drivers and deleterious passengers in tumor growth over a broad range of fitness values and mutation rates. Below a (small) threshold number of drivers tumor growth exhibits a plateau (dormancy) with large burst occurring when a driver achieves fixation, reminiscent of intermittency in dissipative dynamical systems. The predictions of the model, in particular the relationship between the average number of passenger mutations versus drivers in a tumor, is in accord with clinical data on several cancers. When deleterious drivers are included, we predict a non-monotonic growth of tumors as the mutation rate is varied with shrinkage and even reversal occurring at very large mutation rates. This surprising finding explains the paradoxical observation that high chromosomal instability (CIN) correlates with improved prognosis in a number of cancers compared with intermediate CIN.

scholarly journals Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis

2019 ◽  
Vol 20 (19) ◽  
pp. 4799 ◽  
Author(s):  
Zuzanna Nowicka ◽  
Konrad Stawiski ◽  
Bartłomiej Tomasik ◽  
Wojciech Fendler
Keyword(s):  
Head And Neck ◽  
Cancer Progression ◽  
Treatment Options ◽  
Survival Rates ◽  
Chemotherapy Resistance ◽  
Second Primary ◽  
Special Focus ◽  
Primary Tumors ◽  
Extracellular Mirnas ◽  
Extracellular Mirna

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences and second primary tumors remain a great challenge for the clinicians. Presently, there is no biomarker for patient surveillance that could help identify patients with HNSCC that are more likely to experience a relapse or early progression, potentially requiring closer follow-up or salvage treatment. MicoRNAs (miRNAs) are non-coding RNA molecules that posttranscriptionally modulate gene expression. They are highly stable and their level can be measured in biofluids including serum, plasma, and saliva, enabling quick results and allowing for repeated analysis during and after the completion of therapy. This has cemented the role of miRNAs as biomarkers with a huge potential in oncology. Since altered miRNA expression was described in HNSCC and many miRNAs play a role in radio- and chemotherapy resistance, cancer progression, and metastasis, they can be utilized as biomarkers of these phenomena. This review outlines recent discoveries in the field of extracellular miRNA-based biomarkers of HNSCC progression and metastasis, with a special focus on HPV-related cancers and radioresistance.

Abstract 467: Hypertension and Cancer: Are They Related?

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hanh T Tran ◽  
John J Gildea ◽  
Robin A Felder
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Motility ◽  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Cancer Cell Line ◽  
Soft Agar ◽  
Mcf7 Cells ◽  
Link Type

There are literature references supporting a link between hypertension and cancer. However, a mechanism for this association has not been defined. Key players in blood pressure regulation include the dopamine-1 receptor (D 1 R), G protein-coupled kinase type 4 (GRK4) and c-Myc, all found in renal proximal tubule cells (RPTC). c-Myc also regulates GRK4 in the breast cancer cell line MCF7. We hypothesized that the D 1 R would act as a tumor suppressor and both GRK4 and c-Myc as oncogenes in MCF7 cells. GRK4 is positively regulated transcriptionally by c-Myc, and GRK4 is negatively regulated by Caveolin-1 (CAV1) in RPTCs, so we tested if the same relationship occurs in this breast cancer model. SKF38393 (D 1 R agonist, 10μM, 18hr) reduced wild type MCF7 (WT-MCF7) cell motility (an index of aggressive growth) by 16.0% ± 3.2 SEM (n=9; p<0.005; 115393/137330 RFU), while the D 1 R antagonist LE300 (10μM, 18hr) increased cell motility 23.0% ± 7.0 SEM (n=9; p<0.05; 168955/137330 RFU). CAV1, a tumor suppressor and GRK4 kinase inhibitor, is missing in MCF7, so we transfected CAV1 into MCF7 cells (CAV-MCF7) and inhibited cell motility even further following SKF38393 stimulation (29.8% ± 2.8 SEM; n=11; p<0.005 vs.WT-MCF7; 105801/150766 RFU). CAV1 binding to GRK4 was verified by co-immunoprecipitation. CAV-MCF7 also showed higher levels of basal cell surface D 1 R (103.3% ± 35.9 SEM; n=10; p<0.01 vs WT-MCF7; 808/397 RFU) and D 1 R membrane recruitment post-fenoldopam stimulation (FEN, D 1 R agonist, 10μM, 30min) (increase of 65.5% ± 6.18 SEM; n=4; p<0.05 vs. WT-MCF7; 1.65/1.00 RFU). We verified that CAV-MCF7 showed decreased soft agar colony growth and decreased rates of cell proliferation. Because c-Myc increases GRK4 expression, cell proliferation after c-Myc knock down (KD-MCF7) was tested. KD-MCF7 showed decreased cell proliferation at 48 hr by 37.7% ± 7.6 SEM (n=3; p<0.05 vs WT-MCF7; 2752/4416 cells), while both knockdown of c-Myc and re-expression of GRK4 restored proliferation by 23.1% ± 13.4 SEM (n=10; p<0.05 vs KDMCF; 1346/1093 cells) at 96 hr. We therefore conclude that c-Myc activation of GRK4 inactivates the dopaminergic pathway in both the kidney and breast cancer progression which may be a common link between hypertension and breast cancer.

scholarly journals Genetic Interactions in Cancer Progression and Treatment

Cell ◽  
2011 ◽  
Vol 145 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Alan Ashworth ◽  
Christopher J. Lord ◽  
Jorge S. Reis-Filho
Keyword(s):  
Cancer Progression ◽  
Genetic Interactions
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