scholarly journals Germline Structural Variations in Cancer Predisposition Genes

2021 ◽  
Vol 12 ◽  
Author(s):  
Tímea Pócza ◽  
Vince Kornél Grolmusz ◽  
János Papp ◽  
Henriett Butz ◽  
Attila Patócs ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cancer Predisposition ◽  
Detection Methods ◽  
Small Scale ◽  
Structural Variations ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Cancer Syndromes ◽  
Risk Of Cancer

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

scholarly journals Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

2019 ◽  
Vol 16 (8) ◽  
pp. 1427 ◽  
Author(s):  
Declan Timothy Waugh
Keyword(s):  
Enzyme Activity ◽  
Atpase Activity ◽  
Molecular Mechanisms ◽  
Chemical Elements ◽  
Biological Pathways ◽  
Normal Brain ◽  
Biological Interface ◽  
Increased Risk ◽  
And Function ◽  
Risk Of Cancer

In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.

scholarly journals Future of environmental research in the age of epigenomics and exposomics

2017 ◽  
Vol 32 (1-2) ◽  
pp. 45-54 ◽  
Author(s):  
Nina Holland
Keyword(s):  
Public Health ◽  
Molecular Mechanisms ◽  
Environmental Research ◽  
Whole Body ◽  
Epigenetic Mechanisms ◽  
Multifactorial Diseases ◽  
Adverse Health Outcomes ◽  
Increased Risk ◽  
Susceptible Populations ◽  
Risk Of Cancer

Abstract Environmental research and public health in the 21st century face serious challenges such as increased air pollution and global warming, widespread use of potentially harmful chemicals including pesticides, plasticizers, and other endocrine disruptors, and radical changes in nutrition and lifestyle typical of modern societies. In particular, exposure to environmental and occupational toxicants may contribute to the occurrence of adverse birth outcomes, neurodevelopmental deficits, and increased risk of cancer and other multifactorial diseases such as diabetes and asthma. Rapidly evolving methodologies of exposure assessment and the conceptual framework of the Exposome, first introduced in 2005, are new frontiers of environmental research. Metabolomics and adductomics provide remarkable opportunities for a better understanding of exposure and prediction of potential adverse health outcomes. Metabolomics, the study of metabolism at whole-body level, involves assessment of the total repertoire of small molecules present in a biological sample, shedding light on interactions between gene expression, protein expression, and the environment. Advances in genomics, transcriptomics, and epigenomics are generating multidimensional structures of biomarkers of effect and susceptibility, increasingly important for the understanding of molecular mechanisms and the emergence of personalized medicine. Epigenetic mechanisms, particularly DNA methylation and miRNA expression, attract increasing attention as potential links between the genetic and environmental determinants of health and disease. Unlike genetics, epigenetic mechanisms could be reversible and an understanding of their role may lead to better protection of susceptible populations and improved public health.

scholarly journals The Association of Vitamin D with Brain Cognitive Functions: A Literature Review

2020 ◽  
pp. 97-113
Author(s):  
Yahya A. Alzahrani ◽  
Mohammed A. Alomary ◽  
Abdulmajeed A. Alzahrani ◽  
Mawaddah M. Eskandarani ◽  
Iman S. Aljabry ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Current Knowledge ◽  
Neuroprotective Effect ◽  
Cochrane Library ◽  
Calcium Balance ◽  
Increased Risk

Vitamin D is a well-known steroid hormone that plays an important role in controlling bone levels of calcium, phosphorus, and overall mineralization. Several animal and human studies indicate that vitamin D hypovitaminosis may be linked to an increased risk of developing Alzheimer's disease and dementia. The objective of the present review is to summarize current knowledge of the effects of vitamin D deficiency and vitamin D intake on cognitive function. The possible underline mechanisms of these effects were also discussed. We reviewed the literature starting from 1986 to 2019 by searching PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases for all observational studies, randomized clinical trials, meta-analyses, and systematic reviews using the keywords  “vitamin D and Alzheimer disease”, “neuroprotective effect of vitamin D”, “vitamin D deficiency and Alzheimer ”, “role of vitamin D in neurodegenerative diseases ”, ” vitamin D and amyloidogenesis”, “acetylcholine and vitamin D”, and “memory and vitamin D ”.We also referred to animal and in vitro studies that dealt with the possible mechanisms of actions of the neuroprotective effect of vitamin D. Our findings showed that Vitamin D supplementation improves cognitive performance via reducing amyloidogenesis, restoration of neurotransmission, maintaining calcium balance, regulating neurotrophic factors, anti-inflammatory action, apoptosis regulation, antioxidant, and vascular processes. This review might be open new horizons in the understanding of the molecular mechanisms of the disease and neurodegeneration and enable the development of new approaches in treatment and prevention of the disease.

scholarly journals An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

2021 ◽  
Vol 8 ◽  
Author(s):  
Marcella Massimini ◽  
Mariarita Romanucci ◽  
Raffaella De Maria ◽  
Leonardo Della Salda
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Human Cancer ◽  
Vasculogenic Mimicry ◽  
Human Osteosarcoma ◽  
Increased Risk ◽  
Veterinary Pathology ◽  
Canine Tumors ◽  
Novel Biomarkers ◽  
Cancer Types

Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.

The genetics of inherited cancers

2020 ◽  
pp. 456-470
Author(s):  
Rosalind A. Eeles
Keyword(s):  
Relative Risk ◽  
Cancer Risk ◽  
Cancer Genetics ◽  
Clinical Pathways ◽  
Cancer Predisposition ◽  
Cellular Growth ◽  
Increased Risk ◽  
Predisposition Genes ◽  
High Cancer Risk ◽  
Cancer Predisposition Gene

All cancer can be termed ‘genetic’ as the disease is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/or proliferation. Most of these mutations are sporadic (only occurring in the cancer cell), but some are due to the inheritance of a germline mutation in a cancer predisposition gene. Cancer predisposition genes can be rare and confer a high cancer risk (about 10-fold lifetime relative risk), or common and confer a low to moderately increased risk (from just over onefold, up to two- to threefold). They have been shown to be involved in causing some of most common cancers as well as some rare cancers. Cancer genetics will become part of mainstream clinical pathways for cancer care in the coming years and is likely to contribute to healthcare that is tailored to individual patients.

scholarly journals The Emerging Role of Liquid Biopsy in Gastric Cancer

2021 ◽  
Vol 10 (10) ◽  
pp. 2108
Author(s):  
Csongor György Lengyel ◽  
Sadaqat Hussain ◽  
Dario Trapani ◽  
Khalid El Bairi ◽  
Sara Cecilia Altuna ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Liquid Biopsy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
Copy Number Variations ◽  
Quantitative Detection ◽  
Metastatic Setting ◽  
Risk Of Cancer

(1) Background: Liquid biopsy (LB) is a novel diagnostic method with the potential of revolutionizing the prevention, diagnosis, and treatment of several solid tumors. The present paper aims to summarize the current knowledge and explore future possibilities of LB in the management of metastatic gastric cancer. (2) Methods: This narrative review examined the most recent literature on the use of LB-based techniques in metastatic gastric cancer and the current LB-related clinical trial landscape. (3) Results: In gastric cancer, the detection of circulating cancer cells (CTCs) has been recognized to have a prognostic role in all the disease stages. In the setting of localized disease, cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) qualitative and quantitative detection have the potential to inform on the risk of cancer recurrence and metastatic dissemination. In addition, gastric cancer-released exosomes may play an essential part in metastasis formation. In the metastatic setting, the levels of cfDNA show a positive correlation with tumor burden. There is evidence that circulating tumor microemboli (CTM) in the blood of metastatic patients is an independent prognostic factor for shorter overall survival. Gastric cancer-derived exosomal microRNAs or clonal mutations and copy number variations detectable in ctDNA may contribute resistance to chemotherapy or targeted therapies, respectively. There is conflicting and limited data on CTC-based PD-L1 verification and cfDNA-based Epstein–Barr virus detection to predict or monitor immunotherapy responses. (4) Conclusions: Although preliminary studies analyzing LBs in patients with advanced gastric cancer appear promising, more research is required to obtain better insights into the molecular mechanisms underlying resistance to systemic therapies. Moreover, validation and standardization of LB methods are crucial before introducing them in clinical practice. The feasibility of repeatable, minimally invasive sampling opens up the possibility of selecting or dynamically changing therapies based on prognostic risk or predictive biomarkers, such as resistance markers. Research is warranted to exploit a possible transforming area of cancer care.

scholarly journals Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach

2021 ◽  
Vol 12 ◽  
Author(s):  
Pratibha Bhai ◽  
Michael A. Levy ◽  
Kathleen Rooney ◽  
Deanna Alexis Carere ◽  
Jack Reilly ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Hereditary Cancer ◽  
Copy Number ◽  
Copy Number Variants ◽  
Cancer Predisposition ◽  
Sequence Variants ◽  
Predisposition Genes ◽  
Cancer Syndromes ◽  
Generation Sequencing

BackgroundHereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient’s personal and/or family history of cancer.MethodsA 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).ResultsA 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.ConclusionThis study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.

scholarly journals Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered

2022 ◽  
Vol 12 ◽  
Author(s):  
A Losada-García ◽  
SA Cortés-Ramírez ◽  
M Cruz-Burgos ◽  
M Morales-Pacheco ◽  
Carlos D Cruz-Hernández ◽  
...  
Keyword(s):  
Immune System ◽  
Autoimmune Diseases ◽  
Molecular Mechanisms ◽  
Continuous Process ◽  
Clinical Signs ◽  
The Body ◽  
Future Research ◽  
Adaptive Immune ◽  
Increased Risk ◽  
Risk Of Cancer

Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.

Investigating the Biological and Molecular Mechanisms Underpinning the Engraftment/Selection Advantage Conferred to Hematopoietic Stem Cells by HOXB4.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2101-2101
Author(s):  
Michael D. Milsom ◽  
Laura Hollins ◽  
Dorothy Gagen ◽  
Lorna B. Woolford ◽  
Leslie J. Fairbairn
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Vitro Analysis

Abstract We have recently demonstrated that co-expression of HOXB4 enables the enhanced delivery of HSC harbouring a second therapeutic trans-gene. Nonetheless, it is of great importance to elaborate the current knowledge about the mechanism of HOXB4 action in order to both evaluate the safety implications of its use in a clinical strategy, and to gain greater insight into the regulation of HSC self-renewal/expansion. To these ends we have performed an extensive in vitro analysis of the consequences of HOXB4 overexpression in primary murine BMC and in a murine multipotent myeloid progenitor cell line (FDCP-mix). We demonstrate for the first time in murine cells, that ectopic HOXB4 reduces the responsiveness of murine hematopoietic cells to differentiation stimuli. Furthermore, by performing a detailed investigation into the kinetics of FDCP-mix differentiation, we reveal that HOXB4 overexpression results in a specific differentiation delay as opposed to an outright block. We propose that an analogous delay is in operation in repopulating cells in order that the shift to increased assymetrical self-renewal, a requirement for stem cell expansion, is achieved. Notwithstanding this, it is clear that any perturbation in differentiation constitutes an increased risk of cellular transformation if this technology were transferred to a clinical setting. In order to further define the repercussions of ectopic HOXB4 delivery, we have developed a retroviral vector which encodes an activatable version of HOXB4. We have shown that this vector is able to mediate an in vitro differentiation delay in primary murine BMC and FDCP-mix as well as enable enhanced engraftment of BMC in vivo, both dependent upon the addition of the estrogen analogue; tamoxifen. Using this system, we are currently examining the effect of ectopic HOXB4 on the transcriptome of FDCP-mix cells, in addition to performing an in depth study into the biological mechanisms affected by HOXB4 overexpression in BMC in vivo. We envisage that these model systems will be particularly amenable to the manipulation required for target gene identification/validation.

Evaluating the association between clonal hematopoiesis and germline pathogenic and likely pathogenic variants in cancer predisposition genes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1535-1535
Author(s):  
Elizabeth Anne Comen ◽  
Pedram Razavi ◽  
Parth Bhargav Patel ◽  
Axel Martin ◽  
Venkatraman E. Seshan ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Cancer Predisposition ◽  
P Value ◽  
Breast Cancers ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Significant Enrichment ◽  
Relationship Of

1535 Background: Clonal hematopoiesis (CH) is most commonly associated with mutations in genes with a known or putative role in leukemia and with an increased risk for hematologic malignancies. Nearly 50% of primary breast cancers contain leukocytes with CH mutations and CH mutations can be found in breast cancer (BC) tumor infiltrating leukocytes years prior to the development of secondary leukemia. It is currently not known whether CH is more prevalent among BC patients with both germline pathogenic variants and likely pathogenic variants (collectively referred to as PV) in cancer predisposition genes. Here we evaluated the relationship of CH to PV in 546 BC patients (pts). Methods: 546 BC pts underwent targeted capture sequencing of tumor and peripheral blood (PB) samples using MSK-IMPACT. Sequencing results from PB were used for identifying PV affecting up to 89 cancer predisposition genes and somatic mutations in 15 genes commonly associated with CH using previously validated methods. All pts consented via an IRB-approved protocol. Results: The majority (82.3%) of pts had non-metastatic disease. 59.7% of the 546 pts received chemotherapy and 42.7% received radiation. Of the 546 pts, 90 patients had germline PV in a cancer predisposition gene for a total of 98 germline PV identified (8 patients had 2 germline PV). Mutations in DNMT3A followed by TET2 were the most common CH mutations identified. CHEK2 PV were statistically significantly associated with CH in a multivariate analysis after controlling for age, prior chemotherapy and radiation therapy (OR: 3.94, CI: 1.51-10.26, p-value ≤0.005). Age by decade was significantly associated with the presence of CH in that model (OR: 1.93, CI: 1.53-2.42, p value ≤0.001). Of the 8 patients with CHEK2 germline PV and CH, the most common mutated CH genes were DNMT3A (4 pts), followed by TET2 (2 pts), although our sample size is too small to test for significant enrichment for any specific CH gene, type of CH mutation, or trinucleotide context. Further, CH was not associated with germline PV in other cancer predisposition genes. Conclusions: Our findings provide evidence of an association between CHEK2 germline PV with CH in BC pts, which will be further tested in an expanded cohort. If this association is confirmed, it might have theoretical and practical implications, including cancer prevention strategies.

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