scholarly journals Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior

2009 ◽  
Vol 16 (1) ◽  
pp. 291-299 ◽  
Author(s):  
Hans K Ghayee ◽  
Bas Havekes ◽  
Eleonora P M Corssmit ◽  
Graeme Eisenhofer ◽  
Stephen R Hammes ◽  
...  
Keyword(s):  
Aggressive Behavior ◽  
Succinate Dehydrogenase ◽  
Germ Line ◽  
Abdominal Mass ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Clinical Behavior ◽  
Presenting Symptoms ◽  
Catecholamine Excess ◽  
Genes Encoding

Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.

scholarly journals Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl

2010 ◽  
Vol 17 (3) ◽  
pp. 581-588 ◽  
Author(s):  
Maya B Lodish ◽  
Karen T Adams ◽  
Thanh T Huynh ◽  
Tamara Prodanov ◽  
Alex Ling ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Mesenteric Artery ◽  
Chromaffin Cells ◽  
Clinical Characteristics ◽  
Inferior Mesenteric Artery ◽  
Clinical Presentation ◽  
Gene Mutations ◽  
Aortic Bifurcation ◽  
Dehydrogenase Gene ◽  
Genes Encoding

Organ of Zuckerkandl paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from chromaffin cells located around the origin of the inferior mesenteric artery extending to the level of the aortic bifurcation. Mutations in the genes encoding succinate dehydrogenase subunits (SDH) B, C, and D (SDHx) have been associated with PGLs, but their contribution to PGLs of the organ of Zuckerkandl PGLs is not known. We aimed to describe the clinical presentation of patients with PGLs of the organ of Zuckerkandl and investigate the prevalence of SDHx mutations and other genetic defects among them. The clinical characteristics of 14 patients with PGL of the organ of Zuckerkandl were analyzed retrospectively; their DNA was tested for SDHx mutations and deletions. Eleven out of 14 (79%) patients with PGLs of the organ of Zuckerkandl were found to have mutations in the SDHB (9) or SDHD (2) genes; one patient was found to have the Carney–Stratakis syndrome (CSS), and his PGL was discovered during surgery for gastrointestinal stromal tumor. Our results show that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. Patients with PGLs of the organ of Zuckerkandl should be screened for SDHx mutations and the CSS; in addition, asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection.

scholarly journals Succinate Dehydrogenase–Deficient Renal Cell Carcinoma: A Short Review

2018 ◽  
Vol 142 (10) ◽  
pp. 1284-1288 ◽  
Author(s):  
Gang Wang ◽  
Priya Rao
Keyword(s):  
Succinate Dehydrogenase ◽  
Renal Cell ◽  
Germ Line ◽  
Short Review ◽  
Renal Cell Carcinomas ◽  
Characteristic Appearance ◽  
Hereditary Tumor Syndrome ◽  
Eosinophilic Cytoplasm ◽  
Genes Encoding

Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). Germ line mutations of the genes encoding these SDH subunits result in hereditary syndromes harboring pheochromocytomas/paragangliomas, gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-deficient renal cell carcinomas are rare, with a mean age of 38 to 40 years. Histologically, these tumors show a characteristic appearance that includes a solid, nested, or tubular architecture with variable cysts. Cells are typically cuboidal, have indistinct cell borders and eosinophilic cytoplasm, and show flocculent intracytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is the hallmark of these tumors. Although most SDH-deficient renal cell carcinomas are clinically indolent, some tumors may behave aggressively, particularly those with a high nuclear grade, tumor necrosis, or sarcomatoid differentiation. Accurate classification of these tumors is important for clinical follow-up, screening, and genetic evaluation of the patients and other family members for this hereditary tumor syndrome.

Analysis of de novo germline genome mutations

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 63-65
Author(s):  
Mizuki Ohno
Keyword(s):  
Dna Sequences ◽  
De Novo ◽  
Germ Line ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
Cellular Damage ◽  
Base Sequence ◽  
De Novo Mutations ◽  
Basic Genome

Gene mutations are permanent alterations in sections of DNA sequences called genes. This causes a significant and distinguishable change in the base sequence of the affected DNA. They are changes to the base sequence that can occur spontaneously or in response to cellular damage and can vary greatly in size and position, ranging from a single base pair mutation, to changes that span segments of chromosomes, across several genes. Mutations in somatic (non-reproductive) cells are not passed on to the next generation, however germline mutations can occur in germ line cells that can produce egg and sperm, thus causing changes to the basic genome to become fixed in the DNA for future generations to come. This article focuses on germline mutations that are of particular interest to Ohno and her team. Many of these mutations - so called de novo mutations - are genetic alterations present for the first time in one family member as a result of a variation or mutation in a germ cell in either an egg or sperm of one of the parents. DNA repair systems allow for many of the mutations to be prevented and, in reality, only a low level of them become carried forward in the genome. Ohno and her team recognise the causes of germline mutation and are seeking to understand the implications of mutation, with a view to establishing how they may evolve and the possibilities for our future selves. The current human genome is a result of amassed mutations that have accumulated in our genome and driven it along certain pathways to yield what we are now. Ohno is currently working with gene-modified mice but the work is transferable to any mammalian genome, including humans to determine a possible future pathway.

Pannexin channels and their links to human disease

2014 ◽  
Vol 461 (3) ◽  
pp. 371-381 ◽  
Author(s):  
Silvia Penuela ◽  
Luke Harland ◽  
Jamie Simek ◽  
Dale W. Laird
Keyword(s):  
Infectious Diseases ◽  
Human Disease ◽  
Potential Role ◽  
Germ Line ◽  
Disease Onset ◽  
The Other ◽  
Present Review ◽  
Germ Line Mutations ◽  
Genes Encoding ◽  
Intracellular Compartments

In less than a decade, a small family of channel-forming glycoproteins, named pannexins, have captured the interest of many biologists, in large part due to their association with common diseases, ranging from cancers to neuropathies to infectious diseases. Although the pannexin family consists of only three members (Panx1, Panx2 and Panx3), one or more of these pannexins are expressed in virtually every mammalian organ, implicating their potential role in a diverse array of pathophysiologies. Panx1 is the most extensively studied, but features of this pannexin must be cautiously extrapolated to the other pannexins, as for example we now know that Panx2, unlike Panx1, exhibits unique properties such as a tendency to be retained within intracellular compartments. In the present review, we assess the biochemical and channel features of pannexins focusing on the literature which links these unique molecules to over a dozen diseases and syndromes. Although no germ-line mutations in genes encoding pannexins have been linked to any diseases, many cases have shown that high pannexin expression is associated with disease onset and/or progression. Disease may also occur, however, when pannexins are underexpressed, highlighting that pannexin expression must be exquisitely regulated. Finally, we discuss some of the most pressing questions and controversies in the pannexin field as the community seeks to uncover the full biological relevance of pannexins in healthy organs and during disease.

scholarly journals Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Levente Szalárdy ◽  
Dénes Zádori ◽  
Péter Klivényi ◽  
József Toldi ◽  
László Vécsei
Keyword(s):  
Transcriptional Activation ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Cellular Respiration ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Disease Modifying Therapy ◽  
Mitochondrial Functions ◽  
Genes Encoding

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

scholarly journals Genetic Alterations and Their Clinical Implications in Older Patients with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4956-4956
Author(s):  
Cheng-Hong Tsai ◽  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Chin Lin ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
The Elderly ◽  
Genetic Alterations ◽  
Patient Specific ◽  
Intensive Chemotherapy ◽  
P53 Mutations ◽  
Acute Myeloid

Abstract Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315). Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

scholarly journals The Clinical Features and Prognostic Impact of PRDM16 gene Expression in Adult Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5228-5228
Author(s):  
Genki Yamato ◽  
Hiroki Yamaguchi ◽  
Hiroshi Handa ◽  
Norio Shiba ◽  
Satoshi Wakita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Pediatric Aml ◽  
Prdm16 Gene ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a complex disease caused by various genetic alterations. Some prognosis-associated cytogenetic aberrations or gene mutations such as FLT3-internal tandem duplication (ITD), t(8;21)(q22;q22)/RUNX1-RUNX1T1, and inv(16)(p13q22)/CBFB-MYH11 have been found and used to stratify the risk. Numerous gene mutations have been implicated in the pathogenesis of AML, including mutations of DNMT3A, IDH1/2, TET2 and EZH2 in addition to RAS, KIT, NPM1, CEBPA and FLT3in the recent development of massively parallel sequencing technologies. However, even after incorporating these molecular markers, the prognosis is unclear in a subset of AML patients. Recently, NUP98-NSD1 fusion gene was identified as a poor prognostic factor for AML. We have reported that all pediatric AML patients with NUP98-NSD1 fusion showed high expression of the PR domain containing 16 (PRDM16; also known as MEL1) gene, which is a zinc finger transcription factor located near the breakpoint at 1p36. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of EVI1. Furthermore, PRDM16 is essential for hematopoietic stem cell maintenance and remarkable as a candidate gene to induce leukemogenesis. Recent reports revealed that high PRDM16 expression was a significant marker to predict poor prognosis in pediatric AML. However, the significance of PRDM16 expression is unclear in adult AML patients. Methods A total of 151 adult AML patients (136 patients with de novo AML and 15 patients with relapsed AML) were analyzed. They were referred to our institution between 2004 and 2015 and our collaborating center between 1996 and 2013. The median length of follow-up for censored patients was 30.6 months. Quantitative RT-PCR analysis was performed using the 7900HT Fast Real Time PCR System with TaqMan Gene Expression Master Mix and TaqMan Gene Expression Assay. In addition to PRDM16, ABL1 was also evaluated as a control gene. We investigated the correlations between PRDM16 gene expression and other genetic alterations, such as FLT3-ITD, NPM1, and DNMT3A, and clarified the prognostic impact of PRDM16 expression in adult AML patients. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, and the next-generation sequencer Ion PGM. Results PRDM16 overexpression was identified in 29% (44/151) of adult AML patients. High PRDM16 expression correlated with higher white blood cell counts in peripheral blood and higher blast ratio in bone marrow at diagnosis; higher coincidence of mutation in NPM1 (P = 0.003) and DNMT3A (P = 0.009); and lower coincidence of t(8;21) (P = 0.010), low-risk group (P = 0.008), and mutation in BCOR (P = 0.049). Conversely, there were no significant differences in age at diagnosis and sex distribution. Patients with high PRDM16 expression tended to be low frequency in M2 (P = 0.081) subtype, and the remaining subtype had no significant differences between high and low PRDM16 expression. Remarkably, PRDM16 overexpression patients were frequently observed in non-complete remission (55.8% vs. 26.3%, P = 0.001). Patients with high PRDM16 expression tended to have a cumulative incidence of FLT3-ITD (37% vs. 21%, P = 0.089) and MLL-PTD (15% vs. 5%, P = 0.121). We analyzed the prognosis of 139 patients who were traceable. The overall survival (OS) and median survival time (MST) of patients with high PRDM16 expression were significantly worse than those of patients with low expression (5-year OS, 17% vs. 32%; MST, 287 days vs. 673 days; P = 0.004). This trend was also significant among patients aged <65 years (5-year OS, 25% vs. 48%; MST, 361 days vs. 1565 days, P = 0.013). Moreover, high PRDM16 expression was a significant prognostic factor for FLT3-ITD negative patients aged < 65 years in the intermediate cytogenetic risk group (5-year OS, 29% vs. 58%; MST, 215 days vs. undefined; P = 0.032). Conclusions We investigated the correlations among PRDM16 expression, clinical features, and other genetic alterations to reveal clinical and prognostic significance. High PRDM16 expression was independently associated with non-CR and adverse outcomes in adult AML patients, as well as pediatric AML patients. Our finding indicated that the same pathogenesis may exist in both adult and pediatric AML patients with respect to PRDM16 expression, and measuring PRDM16 expression was a powerful tool to predict the prognosis of adult AML patients. Disclosures Inokuchi: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

scholarly journals Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

2019 ◽  
Vol 8 (2) ◽  
pp. 212 ◽  
Author(s):  
Elena Bacchelli ◽  
Eleonora Loi ◽  
Cinzia Cameli ◽  
Loredana Moi ◽  
Ana Vega Benedetti ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Snp Array ◽  
Anion Channel ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Voltage Dependent Anion Channel ◽  
Multiplex Family ◽  
Genes Encoding ◽  
Additional Support

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

scholarly journals Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations

1999 ◽  
Vol 80 (1-2) ◽  
pp. 59-66 ◽  
Author(s):  
A Rashid ◽  
J-S Wang ◽  
G-S Qian ◽  
B-X Lu ◽  
S R Hamilton ◽  
...  
Keyword(s):  
Gene Mutations ◽  
P53 Gene ◽  
Genetic Alterations ◽  
Hepatocellular Carcinomas ◽  
P53 Gene Mutations

scholarly journals A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 147 ◽  
Author(s):  
Carlo Capalbo ◽  
Francesca Belardinilli ◽  
Domenico Raimondo ◽  
Edoardo Milanetti ◽  
Umberto Malapelle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Metastatic Colorectal Cancer ◽  
Gene Mutations ◽  
Bioinformatic Analysis ◽  
Genetic Alterations ◽  
Molecular Heterogeneity ◽  
Clinical Approach ◽  
First Line ◽  
Ras Genes

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

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