scholarly journals Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

2020 ◽  
Author(s):  
Irene Lobon ◽  
Manuel Solis-Moruno ◽  
David Juan ◽  
Ashraf Muhaisen ◽  
Federico Abascal ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Somatic Mutations ◽  
Amplicon Sequencing ◽  
Brain Regions ◽  
Single Nucleotide Variants ◽  
Validation Rate ◽  
Synaptic Functions ◽  
Whole Exome ◽  
Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease.

Exploration of the role of whole exome sequencing variants in -associated Parkinson disease

2021 ◽  
Vol 132 (2) ◽  
pp. S113
Author(s):  
Elizabeth Geena Woo ◽  
Frank Donovan ◽  
Barbara Stubblefield ◽  
Settara Chandrasekharappa ◽  
Grisel Lopez ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome

scholarly journals Genomic and transcriptomic landscape of conjunctival melanoma

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009201
Author(s):  
Katarina Cisarova ◽  
Marc Folcher ◽  
Ikram El Zaoui ◽  
Rosanna Pescini-Gobert ◽  
Virginie G. Peter ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Uv Light ◽  
Point Of View ◽  
Conjunctival Melanoma ◽  
Recurrent Cancer ◽  
Immune Genes ◽  
Whole Exome ◽  
Tumor Tissues

Conjunctival melanoma (CJM) is a rare but potentially lethal and highly-recurrent cancer of the eye. Similar to cutaneous melanoma (CM), it originates from melanocytes. Unlike CM, however, CJM is relatively poorly characterized from a genomic point of view. To fill this knowledge gap and gain insight into the genomic nature of CJM, we performed whole-exome (WES) or whole-genome sequencing (WGS) of tumor-normal tissue pairs in 14 affected individuals, as well as RNA sequencing in a subset of 11 tumor tissues. Our results show that, similarly to CM, CJM is also characterized by a very high mutation load, composed of approximately 500 somatic mutations in exonic regions. This, as well as the presence of a UV light-induced mutational signature, are clear signs of the role of sunlight in CJM tumorigenesis. In addition, the genomic classification of CM proposed by TCGA seems to be well-applicable to CJM, with the presence of four typical subclasses defined on the basis of the most frequently mutated genes: BRAF, NF1, RAS, and triple wild-type. In line with these results, transcriptomic analyses revealed similarities with CM as well, namely the presence of a transcriptomic subtype enriched for immune genes and a subtype enriched for genes associated with keratins and epithelial functions. Finally, in seven tumors we detected somatic mutations in ACSS3, a possible new candidate oncogene. Transfected conjunctival melanoma cells overexpressing mutant ACSS3 showed higher proliferative activity, supporting the direct involvement of this gene in the tumorigenesis of CJM. Altogether, our results provide the first unbiased and complete genomic and transcriptomic classification of CJM.

scholarly journals The potential role of neuroinflammation and transcription factors in Parkinson disease

2017 ◽  
Vol 19 (1) ◽  
pp. 71-80 ◽  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Substantia Nigra ◽  
Parkinson Disease ◽  
Signaling Pathways ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Death Domain

Parkinson disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurons affected by inflammatory processes. Post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines, confirming an ongoing neuroinflammation in the affected brain regions. These inflammatory mediators may activate transcription factors—notably nuclear factor κB, Ying-Yang 1 (YY1), fibroblast growth factor 20 (FGF20), and mammalian target of rapamycin (mTOR)—which then regulate downstream signaling pathways that in turn promote death of dopaminergic neurons through death domain-containing receptors. Dopaminergic neurons are vulnerable to oxidative stress and inflammatory attack. An increased level of inducible nitric oxide synthase observed in the substantia nigra and striatum of PD patients suggests that both cytokine—and chemokine-induced toxicity and inflammation lead to oxidative stress that contributes to degeneration of dopaminergic neurons and to disease progression. Lipopolysaccharide activation of microglia in the proximity of dopaminergic neurons in the substantia nigra causes their degeneration, and this appears to be a selective vulnerability of dopaminergic neurons to inflammation. In this review, we will look at the role of various transcription factors and signaling pathways in the development of PD.

Genomic predictors of neoadjuvant chemotherapy (NACT) response in breast cancer (BC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12122-e12122 ◽  
Author(s):  
Andrea Li Ann Wong ◽  
Kar Tong Tan ◽  
Raghav Sundar ◽  
Samuel Ow ◽  
Angela Pang ◽  
...  
Keyword(s):  
Low Dose ◽  
Somatic Mutations ◽  
Target Lesion ◽  
Driver Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Mutant Variant ◽  
Poor Outcomes ◽  
Clinical Trial Information

e12122 Background: We assessed effects of NACT on BC mutational landscape. Methods: Baseline (BL) and post-NACT tumor / matched normal DNA from 12 newly diagnosed BC patients on NACT (4 x doxorubicin/cyclophosphamide + low dose sunitinib; NCT01176799) were subject to whole exome sequencing. Nonsynonymous somatic single nucleotide variants from 34 genes in known BC signaling pathways were evaluated for changes in mutant variant allele frequency (VAF) according to clinical outcome. Poor outcome was defined as <50% target lesion reduction after NACT or BC relapse / progression (PD) within 2 years; significant change was defined as > 0.2 difference in BL vs post-NACT mutant VAF. Results: Mean tumor size was 6.4 + 2.9cm; 50% were N+; 8% were M1; 7/12 patients had poor outcomes. Tumors harbored mutations in PI3K (58%), NOTCH (42%), Wnt (42%), TP53 (33%) and FOXA (17%) pathways. Change in no. of somatic mutations post-NACT correlated with outcome (mean percent change +14% vs -30% in patients with poor vs good outcome, p=0.04). 11 patients had >1 of 23 putative driver mutations identified ( Table 1). Mutant VAF declined significantly in those with good outcomes, except for a new NOTCH2 mutation in A2 and rise in mutant VAF in A4. In patients with poor outcomes, mutant VAF persisted or rose, and emergent mutations (AKT1, PIK3CA) occurred in 2 patients. Conclusions: Chemoresistance and emergent mutations were revealed by tracking mutant VAF in BC patients on NACT. Clinical trial information: NCT01176799. [Table: see text]

Whole-exome sequencing in radically resected gastric cancer (GC): Analysis of patients (pts) with poor prognostic factors from the Italian Trial of Adjuvant Chemotherapy Adenocarcinoma (ITACA-S) trial.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 64-64
Author(s):  
Maria Di Bartolomeo ◽  
Devecchi Andrea ◽  
Silvana Canevari ◽  
Alessandro Pellegrinelli ◽  
Filippo Pietrantonio ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Gastroesophageal Junction ◽  
Nodal Involvement ◽  
Single Nucleotide Variants ◽  
Whole Exome ◽  
Relevant Role ◽  
Formalin Fixed Paraffin Embedded ◽  
Ajcc Staging

64 Background: At present, the clinical management of resected GC is only based on risk stratification according to the AJCC staging. This project evaluates molecular factors on formalin-fixed, paraffin-embedded (FFEP) specimens of the primary tumor radically resected in an omogeneous group patients considered at poor prognosis according by nodal involvement (pN3a/b AJCC 7th edition) and included in the ITACA-S trial. Methods: Matched pairs of tumor-normal GC FFPE specimens collected from 15 patients were subjected to whole-exome sequencing using TruSeq Exome technology and NextSeq500 (Illumina). Somatic mutations (single-nucleotide variants) were identified, filtered and then searched for recurrently mutated genes and pathways. Patients with recurrence (cases) were compared to an equally-sized sample of patients without recurrence (controls) with the same follow up time (60 months). Results: Clinical characteristics of 15 pts: median age 61 (41-71) yrs. Nodal involvement: pN3a( 5); pN3b (10). Histotype: Intestinal (4); diffuse (8); mixed (3). Primary site: gastroesophageal junction (1); gastric (14). Patients with GC relapse (8) and without relapse (7). Whole exome sequencing revealed the presence of an average of 553 somatic mutations (range: 197 - 1318) following removal of not exonic/silent variants and of variants with an alternative allele depth < 5. Among a list of 48 genes, reported as mutated in some GC studies, we found that CDH1, GNAS and DCC were mutated in 57% of patients, whereas CTNNB1, LRP1B, LRRK2, NOTCH1, and TRRAP were mutated in 42%. Furthermore RHOA, KRAS, FGFR2, PDGFRA and PRKDC showed mutation in 28% of cases. We are currently evaluating the presence of mutual exclusive relationships mechanisms, functions and molecular pathways in “cases” versus “controls”. Conclusions: Our findings confirm a relevant role of disregulation of cell adhesion pathway involving CDH1 and DCC in GC. However, a validation analysis with an independent and bigger cohort of GC patients is ongoing, in order to find outcome-related mutational patterns that could be relevant for the selection of treatment in GC.

scholarly journals Investigation of somatic mutations in human brains targeting genes associated with Parkinson's disease

2020 ◽  
Author(s):  
Melissa Leija-Salazar ◽  
Alan Pittman ◽  
Katya Mokretar ◽  
Huw Morris ◽  
Anthony HV Schapira ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Monozygotic Twin ◽  
Brain Regions ◽  
Somatic Variation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Somatic Variant ◽  
Lrrk2 G2019s ◽  
Variant Detection ◽  
Human Brains

Background: Somatic mutations occur in neurons but their role in synucleinopathies is unknown. Aim: We aimed to identify disease-relevant low-level somatic single nucleotide variants (SNVs) in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation. Methods and Results: We included different brain regions from 26 Parkinsons disease (PD), 1 Incidental Lewy body, 3 multiple system atrophy cases and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33-5% allele frequencies for validation using accurate methods for somatic variant detection. Conclusions: We could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.

scholarly journals Genetic Factors in Rasmussen’s Encephalitis Characterized by Whole-Exome Sequencing

2021 ◽  
Vol 15 ◽  
Author(s):  
Junhong Ai ◽  
Yisong Wang ◽  
Dong Liu ◽  
Dongying Fan ◽  
Qiqi Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Adaptive Immunity ◽  
Whole Exome Sequencing ◽  
Genetic Factors ◽  
Epileptic Seizures ◽  
Single Nucleotide Variants ◽  
Rasmussen’S Encephalitis ◽  
Whole Exome ◽  
Complex Adaptive

Rasmussen’s encephalitis (RE) is a rare chronic neurological disorder characterized by unihemispheric brain atrophy and epileptic seizures. The mechanisms of RE are complex. Adaptive immunity, innate immunity and viral infection are all involved in the development of RE. However, there are few studies on the role of genetic factors in the mechanisms of RE. Thus, the objective of this study was to reveal the genetic factors in the mechanisms of RE. Whole-exome sequencing (WES) was performed in 15 RE patients. Ten patients with temporal lobe epilepsy (TLE), which is a common and frequently intractable seizure disorder, were used as the controls. Thirty-one non-silent single nucleotide variants (SNVs) affecting 16 genes were identified in the RE cases. The functions of the genes with SNVs were associated with antigen presentation, antiviral infection, epilepsy, schizophrenia and nerve cell regeneration. Genetic factors of RE were found first in this study. These results suggest that RE patients have congenital abnormalities in adaptive immunity and are susceptible to some harmful factors, which lead to polygenic abnormal disease.

scholarly journals Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

2020 ◽  
Vol 4 (10) ◽  
Author(s):  
Juilee Rege ◽  
Kazutaka Nanba ◽  
Amy R Blinder ◽  
Samuel Plaska ◽  
Aaron M Udager ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Early Onset ◽  
Somatic Mutations ◽  
Amplicon Sequencing ◽  
Driver Mutations ◽  
Type Ii ◽  
Voltage Gated ◽  
Germline Variant ◽  
Whole Exome ◽  
Aldosterone Production

Abstract Somatic mutations driving aldosterone production have been identified in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected 2 somatic variants in CLCN2 in 2 APAs that were negative for currently known aldosterone-driver mutations. The CLCN2 gene encodes the voltage-gated chloride channel ClC-2. CLCN2 germline variants have previously been shown to cause familial hyperaldosteronism type II. Somatic mutations in CLCN2 were identified in 2 of 115 APAs, resulting in a prevalence of 1.74%. One of the CLCN2 somatic mutations (c.G71A,p.G24D) was identical to a previously described germline variant causing early-onset PA, but was present only as a somatic mutation. The second CLCN2 mutation, which affects the same region of the gene, has not been reported previously (c.64-2_74del). These findings prove that WES of CYP11B2-guided mutation-negative APAs can help determine rarer genetic causes of sporadic PA.

scholarly journals Genomics Links Inflammation with Neurocognitive Impairment in Children Living with Human Immunodeficiency Virus type-1

2020 ◽  
Author(s):  
Pratima Rawat ◽  
Sean S Brummel ◽  
Kumud K Singh ◽  
Jihoon Kim ◽  
Kelly A Frazer ◽  
...  
Keyword(s):  
Neurocognitive Impairment ◽  
Single Nucleotide Variants ◽  
Discovery Cohort ◽  
Single Nucleotide ◽  
Human Microglia ◽  
Whole Exome ◽  
Increased Risk ◽  
Immunodeficiency Virus

Abstract Background We identified host single nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children. Methods Whole exome sequencing (WES) was performed on 217 PHIV with NCI (cognitive score for age (CSA) &lt;70 and 247 CSA &gt; 70 (Discovery Cohort [DC]). SNVs identified in DC were evaluated in two validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes. Results 29 SNVs in 24 genes reaching p ≤0.002 and OR ≥1.5 comparing CSA &lt;70 to CSA ≥70 were identified in the DC of which three SNVs were identified in VC1 and VC2 for further study. Combining the three cohorts, a SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (p&lt;0.0001) whereas RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (p&lt;0.0001 and P&lt;0.001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1β following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1β release. Conclusions Using WES and two VCs, and gene silencing of microglia we identified three genetic variants that are associated with NCI and inflammation in HIV-infected children.

The Platelet and The Neuron: Two Cells in Focus in Migraine

Cephalalgia ◽  
1988 ◽  
Vol 8 (1) ◽  
pp. 7-24 ◽  
Author(s):  
Rigmor Malmgren ◽  
Lena Hasselmark
Keyword(s):  
Migraine Attack ◽  
Clinical Significance ◽  
Platelet Function ◽  
Serotonergic Neurons ◽  
Stimulus Response ◽  
Investigative Tool ◽  
Synaptic Functions ◽  
Neuronal Processes ◽  
Platelet Functions

Reports of platelet abnormalities in migraine are abundant, and the present paper discusses the role of platelets in the migraine aetiology. Platelets are considered good models for pre-and post-synaptic functions in serotonergic neurons. We propose that migraine is associated with a lowered threshold for stimulus response in both platelets and serotonergic neurons and that the alterations in platelet function reflect central serotonergic disturbances. The platelet abnormalities in migraine approach those found in depression, and there are several links between the two disorders. The clinical significance of platelet hyperactivity in migraineurs for the occurrence of thrombotic disorders is also discussed. Studies of platelet functions in migraine, using platelets as models for serotonergic neurons, may broaden our understanding of the neuronal processes that take place during a migraine attack. The platelet can also be an investigative tool for better understanding of the modes of action of anti-migraine drugs.

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