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Cancer Science Nov 2004BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive... (Review)
Review
BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apoptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphorylation events; however, the extent to which phosphorylation-activated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.
Topics: Apoptosis; Breast Neoplasms; Cell Cycle; DNA Damage; DNA Repair; Female; Gene Expression Regulation, Neoplastic; Genes, BRCA1; Genes, BRCA2; Humans; Mutation; Ovarian Neoplasms; Phosphorylation; Transcription, Genetic
PubMed: 15546503
DOI: 10.1111/j.1349-7006.2004.tb02195.x -
Cellular Physiology and Biochemistry :... 2018Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive... (Review)
Review
Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson's two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.
Topics: Alleles; Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Mutation; Neoplasms; Proteolysis; Tumor Suppressor Proteins; Ubiquitination
PubMed: 30562755
DOI: 10.1159/000495956 -
BioEssays : News and Reviews in... Dec 2015Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins... (Review)
Review
Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.
Topics: Antineoplastic Agents; Drug Discovery; Genes, Tumor Suppressor; Genomics; Humans; Mutation; Neoplasms
PubMed: 26445307
DOI: 10.1002/bies.201500093 -
Cell Stem Cell May 2020Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional...
Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional identification of tumor drivers, we developed a platform for pooled CRISPR-Cas9 screening in human colon organoids. Using transforming growth factor β (TGF-β) resistance as a paradigm to establish sensitivity and scalability in vitro, we identified optimal conditions and strict guide RNA (gRNA) requirements for screening in 3D organoids. We then screened a pan-cancer tumor suppressor gene (TSG) library in pre-malignant organoids with APC;KRAS mutations, which were xenografted to study clonal advantages in context of a complex tumor microenvironment. We identified TGFBR2 as the most prevalent TSG, followed by known and previously uncharacterized mediators of CRC growth. gRNAs were validated in a secondary screen using unique molecular identifiers (UMIs) to adjust for clonal drift and to distinguish clone size and abundance. Together, these findings highlight a powerful organoid-based platform for pooled CRISPR-Cas9 screening for patient-specific functional genomics.
Topics: CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Genes, Tumor Suppressor; Humans; Organoids
PubMed: 32348727
DOI: 10.1016/j.stem.2020.04.003 -
The New England Journal of Medicine Mar 2008
Review
Topics: DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Genetic Therapy; Histones; Humans; MicroRNAs; Neoplasms; Prognosis; Promoter Regions, Genetic
PubMed: 18337604
DOI: 10.1056/NEJMra072067 -
Annual Review of Genomics and Human... Aug 2022A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a... (Review)
Review
A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-, , , , , , , and -and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.
Topics: Genes, Tumor Suppressor; Humans; Mosaicism; Mutation; Phenotype; Prevalence
PubMed: 36044908
DOI: 10.1146/annurev-genom-120121-105450 -
Molecular Cancer Dec 2014LRRC4/NGL-2 (Leucine rich repeat containing 4/Netrin-G ligand-2), a relatively specific expressed gene in brain tissue, is a member of the LRRC4/ NGL (netrin-G ligand)... (Review)
Review
LRRC4/NGL-2 (Leucine rich repeat containing 4/Netrin-G ligand-2), a relatively specific expressed gene in brain tissue, is a member of the LRRC4/ NGL (netrin-G ligand) family and belongs to the superfamily of LRR proteins. LRRC4/NGL-2 regulates neurite outgrowth and lamina-specific dendritic segmentation, suggesting that LRRC4/NGL-2 is important for the development of the nervous system. In addition, LRRC4/NGL-2 has been identified as a tumor suppressor gene. The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. LRRC4/NGL-2 also has the ability to form multiphase loops with miRNA, transcription factors and gene methylation modification; the loss of LRRC4/NGL-2 function may be an important event in multiple biological processes in gliomas. In summary, LRRC4/NGL-2 is a critical gene in the normal development and tumorigenesis of the nervous system.
Topics: Carcinogenesis; Cell Proliferation; Genes, Tumor Suppressor; Glioma; Humans; Neovascularization, Pathologic; Nerve Tissue Proteins
PubMed: 25526788
DOI: 10.1186/1476-4598-13-266 -
Panminerva Medica Dec 2015Bladder cancer is amongst the most common malignant tumor of the urinary tract system and has the worst outcomes. The factors related to the occurrence and progression... (Review)
Review
Bladder cancer is amongst the most common malignant tumor of the urinary tract system and has the worst outcomes. The factors related to the occurrence and progression of this urological cancer has received considerable research attention. The discovery of marker genes enhances the sensitivity and specificity of early diagnosis and treatment of bladder cancer. Furthermore, these genes can be used as targets for antitumor drugs. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis could improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Several studies on the biological characters and mechanism of the related proteins have provided a theoretical basis for the diagnosis and treatment of bladder cancer. In this review article, we summarized the status of the current studies in this field.
Topics: Biomarkers, Tumor; Genes, Tumor Suppressor; Humans; Oncogenes; Urinary Bladder Neoplasms
PubMed: 25634585
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Dec 2014The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not... (Review)
Review
The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not the most fragile locus in epithelial cells, the cell of origin for most Fhit-negative cancers, eroding support for past claims that deletions at this locus are simply passenger events that are carried along in expanding cancer clones, due to extreme vulnerability to DNA damage rather than to loss of FHIT function. Indeed, recent reports have reconfirmed FHIT as a tumor suppressor gene with roles in apoptosis and prevention of the epithelial-mesenchymal transition. Other recent works have identified a novel role for the FHIT gene product, Fhit, as a genome "caretaker." Loss of this caretaker function leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks. Because Fhit loss-induced DNA damage is "checkpoint blind," cells accumulate further DNA damage during subsequent cell cycles, accruing global genome instability that could facilitate oncogenic mutation acquisition and expedite clonal expansion. Loss of Fhit activity therefore induces a mutator phenotype. Evidence for FHIT as a mutator gene is discussed in light of these recent investigations of Fhit loss and subsequent genome instability.
Topics: Acid Anhydride Hydrolases; Animals; Cell Cycle; DNA Damage; DNA Replication; Epithelial-Mesenchymal Transition; Genes, Tumor Suppressor; Genomic Instability; Humans; Neoplasm Proteins; Neoplasms
PubMed: 25283145
DOI: 10.1007/s00018-014-1722-0 -
Discovery Medicine Jan 2016Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent... (Review)
Review
Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent mutations in tumor suppressor genes. While targeted therapeutics increasingly are being investigated in head and neck cancer, the majority of these agents are against overactive/overexpressed oncogenes. Therapy to restore lost tumor suppressor gene function remains a key and under-addressed niche in trials for head and neck cancer. Recent advances in gene editing have captured the interest of both the scientific community and the public. As our technology for gene editing and gene expression modulation improves, addressing lost tumor suppressor gene function in head and neck cancers is becoming a reality. This review will summarize new techniques, challenges to implementation, future directions, and ethical ramifications of gene therapy in head and neck cancer.
Topics: Animals; Carcinoma, Squamous Cell; Genes, Tumor Suppressor; Genetic Therapy; Head and Neck Neoplasms; Humans
PubMed: 26896601
DOI: No ID Found