scholarly journals The future: genetics advances in MEN1 therapeutic approaches and management strategies

2017 ◽  
Vol 24 (10) ◽  
pp. T119-T134 ◽  
Author(s):  
Sunita K Agarwal
Keyword(s):  
Genetic Testing ◽  
Tumor Suppressor ◽  
Mouse Models ◽  
Target Genes ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Dimensional Structure

The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in theMEN1gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of theMEN1gene in MEN1-target tissues. Therefore,MEN1is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by theMEN1gene, menin, holds true in mouse models with germline heterozygousMen1loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of theMen1gene. The availability of genetic testing for mutations in theMEN1gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identifyMEN1germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.

Genetic Events Responsible for Colorectal Tumorigenesis: Achievements and Challenges

1993 ◽  
Vol 79 (4) ◽  
pp. 235-243 ◽  
Author(s):  
Boris Kopnin
Keyword(s):  
Tumor Suppressor ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Colorectal Carcinogenesis ◽  
Genetic Changes ◽  
Colorectal Tumorigenesis ◽  
Ras Genes ◽  
Carcinoma Cell Lines ◽  
Kinase C ◽  
Multistep Process

Colorectal carcinogenesis is a multistep process that is accompanied by accumulation of changes in proto-oncogenes and tumor-suppressor genes. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes, as well as other genomic alterations appear at characteristic stages of tumor development and are observed in most neoplasms. However, consideration of each of these abnormalities leaves many unanswered questions. The striking data on recurrent amplification of the RB tumor-suppressor gene as well as suppressive activities of protein kinase C and activated RAS genes, at least in some colon carcinoma cell lines, suggest the unusual effects of some signalling pathways in colonic epithelial cells. The results obtained to date indicate that distinct sets of genetic changes may underlie the development of colorectal tumors.

Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma

1996 ◽  
Vol 84 (5) ◽  
pp. 847-851 ◽  
Author(s):  
Takehiko Harada ◽  
Richard M. Irving ◽  
John H. Xuereb ◽  
David E. Barton ◽  
David G. Hardy ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Neurofibromatosis Type ◽  
Suppressor Gene ◽  
Neurofibromatosis Type 2 ◽  
Chromosome 22 ◽  
Sporadic Meningioma

✓ The authors investigated the role of somatic mutations of the neurofibromatosis type 2 (NF2) gene in sporadic meningioma. Neurofibromatosis 2 is a dominantly inherited familial tumor syndrome predisposing affected patients to a variety of central nervous system tumors including vestibular schwannoma and meningioma. Neurofibromatosis type 2 is caused by germline mutations in the NF2 tumor suppressor gene. In addition, the authors and others have reported that somatic NF2 gene mutations occur frequently in nonfamilial vestibular schwannoma. In this study, molecular genetic analysis was performed on 23 nonfamilial meningiomas. Paired DNA samples extracted from the blood and tumors of the patients were analyzed for loss of heterozygosity (LOH) in the region of the NF2 gene on chromosome 22 using closely linked DNA markers. The NF2 gene mutations were sought by single-stranded conformation polymorphism analysis and DNA sequencing. Fourteen (61%) of 23 meningiomas showed LOH in the region of the NF2 gene on chromosome 22. Somatic NF2 gene mutations were detected in eight meningiomas (35%) after screening all 17 exons. All tumors with NF2 gene mutations showed simultaneous chromosome 22 LOH. Review of the histopathological findings of the cases studied did not demonstrate any predominance of genetic abnormalities in a particular histological type of meningioma. These results are compatible with the hypothesis that the NF2 gene acts as a tumor suppressor and that its inactivation is important in the pathogenesis of sporadic meningioma.

scholarly journals Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 552-565 ◽  
Author(s):  
DM Knowles ◽  
E Cesarman ◽  
A Chadburn ◽  
G Frizzera ◽  
J Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Gene Rearrangement ◽  
Molecular Genetic ◽  
Suppressor Gene ◽  
Lymphoproliferative Disorders ◽  
Ebv Infection ◽  
P53 Tumor Suppressor Gene ◽  
Single Form ◽  
Gene Alterations

Abstract The posttransplantation lymphoproliferative disorders (PT-LPDs) are a morphologically heterogeneous group of Epstein-Barr virus (EBV)-driven lymphoid proliferations of varying clonal composition. Some PT-LPDs regress after a reduction in immunosuppression, while others progress in spite of aggressive therapy. Previously defined morphologic categories do not correlate with clonality, and neither morphology nor clonality has reliably predicted the clinical behavior of PT-LPDs. We investigated 28 PT-LPD lesions occurring in 22 patients for activating alterations involving the bcl-1, bcl-2, c-myc, and H-, K- and N-ras proto-oncogenes and for mutations involving the p53 tumor suppressor gene. We correlated the results of these studies with the morphology of the lesions, their clonality based on Ig heavy and light chain gene rearrangement analysis, and the presence and clonality of EBV infection. We found that the PT-LPDs are divisible into three distinct categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infection events or only a minor cell population infected by a single form of EBV, and lack oncogene and tumor suppressor gene alterations; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma: may arise in lymph nodes or various extranodal sites, are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene alterations; and (3) immunoblastic lymphoma or multiple myeloma: present with widely disseminated disease, are monoclonal, contain a single form of EBV, and contain alterations of one or more oncogene or tumor suppressor genes (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement). The PT-LPDs are divisible into three categories exhibiting distinct morphologic and molecular genetic characteristics. Alterations involving the N-ras and c-myc proto- oncogenes and the p53 tumor suppressor gene may play an important role in the development and/or progression of the PT-LPDs.

scholarly journals The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0145792 ◽  
Author(s):  
Wendy M. McKimpson ◽  
Ziqiang Yuan ◽  
Min Zheng ◽  
Judy S. Crabtree ◽  
Steven K. Libutti ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Tissue Specific ◽  
Specific Manner

scholarly journals Complete In Vitro Assembly of the Reovirus Outer Capsid Produces Highly Infectious Particles Suitable for Genetic Studies of the Receptor-Binding Protein

2001 ◽  
Vol 75 (11) ◽  
pp. 5335-5342 ◽  
Author(s):  
Kartik Chandran ◽  
Xing Zhang ◽  
Norman H. Olson ◽  
Stephen B. Walker ◽  
James D. Chappell ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Cell Attachment ◽  
Molecular Genetic ◽  
Three Dimensional ◽  
Host Cells ◽  
Dimensional Structure ◽  
Dependent Manner ◽  
Viral Attachment ◽  
Structure Assembly

ABSTRACT Mammalian reoviruses, prototype members of theReoviridae family of nonenveloped double-stranded RNA viruses, use at least three proteins—ς1, μ1, and ς3—to enter host cells. ς1, a major determinant of cell tropism, mediates viral attachment to cellular receptors. Studies of ς1 functions in reovirus entry have been restricted by the lack of methodologies to produce infectious virions containing engineered mutations in viral proteins. To mitigate this problem, we produced virion-like particles by “recoating” genome-containing core particles that lacked ς1, μ1, and ς3 with recombinant forms of these proteins in vitro. Image reconstructions from cryoelectron micrographs of the recoated particles revealed that they closely resembled native virions in three-dimensional structure, including features attributable to ς1. The recoated particles bound to and infected cultured cells in a ς1-dependent manner and were approximately 1 million times as infectious as cores and 0.5 times as infectious as native virions. Experiments with recoated particles containing recombinant ς1 from either of two different reovirus strains confirmed that differences in cell attachment and infectivity previously observed between those strains are determined by the ς1 protein. Additional experiments showed that recoated particles containing ς1 proteins with engineered mutations can be used to analyze the effects of such mutations on the roles of particle-bound ς1 in infection. The results demonstrate a powerful new system for molecular genetic dissections of ς1 with respect to its structure, assembly into particles, and roles in entry.

scholarly journals Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

2008 ◽  
Vol 6 ◽  
pp. CIN.S618 ◽  
Author(s):  
Rachel Karchin ◽  
Mukesh Agarwal ◽  
Andrej Sali ◽  
Fergus Couch ◽  
Mary S. Beattie
Keyword(s):  
Genetic Testing ◽  
Protein Structure ◽  
Tumor Suppressor ◽  
Likelihood Ratio ◽  
Cancer Susceptibility ◽  
Suppressor Gene ◽  
Medical Genetics ◽  
Missense Mutations ◽  
Likelihood Ratios ◽  
The Impact

Background Missense (amino-acid changing) variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1) interpreting the medical relevance of predictive scores is difficult; 2) the relationship between bioinformatics “predictors” (sequence conservation, protein structure) and cancer susceptibility is not understood. Methodology/Principal Findings We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [ 1 ]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general. Conclusions/Significance Missense mutations are the most common disease-producing genetic variants. We present a fast, scalable bioinformatics method that integrates information about protein sequence, conservation, and structure in a likelihood ratio that can be integrated with medical genetics likelihood ratios. The protein likelihood ratio, together with medical genetics likelihood ratios, can be used by clinicians and counselors to communicate the relevance of a VUS to the individual who has that VUS. The approach described here is generalizable to regions of any tumor suppressor gene that have been structurally determined by X-ray crystallography or for which a protein homology model can be built.

Role of VHL Gene Mutation in Human Cancer

2004 ◽  
Vol 22 (24) ◽  
pp. 4991-5004 ◽  
Author(s):  
William Y. Kim ◽  
William G. Kaelin
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Human Cancer ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Von Hippel Lindau

Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear-cell renal carcinomas. The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation of hypoxia-inducible factor (HIF), plays a central role in the mammalian oxygen-sensing pathway. This interaction between pVHL and HIF is governed by post-translational prolyl hydroxylation of HIF in the presence of oxygen by a conserved family of Egl-nine (EGLN) enzymes. In the absence of pVHL, HIF becomes stabilized and is free to induce the expression of its target genes, many of which are important in regulating angiogenesis, cell growth, or cell survival. Moreover, preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma. On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF.

scholarly journals Associating disease-related genetic variants in intergenic regions to the genes they impact

2014 ◽  
Author(s):  
Geoff Macintyre ◽  
Antonio Jimeno Yepes ◽  
Cheng Soon Ong ◽  
Karin Verspoor
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Three Dimensional ◽  
Biomedical Literature ◽  
Dimensional Structure ◽  
Chromatin Conformation ◽  
Functional Interpretation ◽  
Chromatin Conformation Capture ◽  
Intergenic Regions ◽  
Small Test

We present a method to assist in interpretation of the functional impact of intergenic disease-associated SNPs that is not limited to search strategies proximal to the SNP. The method builds on two sources of external knowledge: the growing understanding of three-dimensional spatial relationships in the genome, and the substantial repository of information about relationships among genetic variants, genes, and diseases captured in the published biomedical literature. We integrate chromatin conformation capture data (HiC) with literature support to rank putative target genes of intergenic disease-associated SNPs. We demonstrate that this hybrid method outperforms a genomic distance baseline on a small test set of expression quantitative trait loci, as well as either method individually. In addition, we show the potential for this method to uncover relationships between intergenic SNPs and target genes across chromosomes. With more extensive chromatin conformation capture data becoming readily available, this method provides a way forward towards functional interpretation of SNPs in the context of the three dimensional structure of the genome in the nucleus.

Tumor Suppressor Gene Smad4/DPC4, Its Downstream Target Genes, and Regulation of Cell Cyclea

1999 ◽  
Vol 880 (1 CELL AND MOLE) ◽  
pp. 31-37 ◽  
Author(s):  
PAUL J. CHIAO ◽  
KELLY K. HUNT ◽  
ANA M. GRAU ◽  
ARAM ABRAMIAN ◽  
JASON FLEMING ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Target Genes ◽  
Suppressor Gene ◽  
Downstream Target
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