scholarly journals MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONIC HEDGEHOG MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii392-iii393
Author(s):  
Giles W Robinson ◽  
Sebastian M Waszak ◽  
Brian L Gudenas ◽  
Kyle S Smith ◽  
Antoine Forget ◽  
...  
Keyword(s):  
Pedigree Analysis ◽  
P Value ◽  
Control Analysis ◽  
Loss Of Function ◽  
Protein Coding ◽  
Germline Variants ◽  
Elongator Complex ◽  
Predisposition Genes ◽  
The Unfolded Protein Response ◽  
Case Control Analysis

Abstract BACKGROUND Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes. METHODS Case-control analysis performed on 795 MB patients against >118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB. RESULTS Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response. CONCLUSIONS We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.

scholarly journals ATRT-11. PREVALENCE OF GERMLINE VARIANTS IN SMARCB1 INCLUDING SOMATIC MOSAICISM IN AT/RT AND OTHER RHABDOID TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii277-iii278
Author(s):  
Ryota Shirai ◽  
Tomoo Osumi ◽  
Keita Terashima ◽  
Chikako Kiyotani ◽  
Meri Uchiyama ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Snp Array ◽  
Somatic Mosaicism ◽  
Low Frequency ◽  
Rhabdoid Tumor ◽  
Loss Of Function ◽  
Germline Mosaicism ◽  
Germline Variants ◽  
Predisposition Genes ◽  
Rhabdoid Tumors

Abstract BACKGROUND Genetic hallmark of atypical teratoid/rhabdoid tumor (AT/RT) is loss-of-function variants or deletions in SMARCB1 gene on 22q11.2 chromosome, which is common to extracranial malignant rhabdoid tumors (MRT). Previous studies demonstrated that approximately one-thirds of AT/RT and extracranial MRT patients harbored germline SMARCB1 variants as the rhabdoid tumor predisposing syndrome. We studied herein intensive analysis of the SMARCB1 gene in AT/RT and extracranial MRT patients focusing on prevalence of germline genetic variants. PROCEDURE: In total, 16 patients were included. Both tumor-derived DNA and germline DNA were obtained from all patients. First, screening for SMARCB1 alterations in the tumor specimens was done by direct sequencing, ddPCR and SNP array analysis. Then, analysis of germline DNA samples focusing on the genomic abnormalities detected in the paired tumors in each case was performed. RESULTS In eight of 16 cases (50%), genomic alterations observed in the tumor-derived DNA were also detected in the germline DNA. It is worth noting that three patients had germline mosaicism. Two of three patients had mosaic deletion, including SMARCB1 region, and the average copy number of the deleted region in the SMARCB1 gene in the germline was 1.60 and 1.76. For another patient, the fraction of SMARCB1 variants in normal cells was as low as 1.7%. CONCLUSIONS Approximately half the MRT cases in this study had SMARCB1 germline alterations. Considering the presence of low-frequency mosaicisms which conventional methods might overlook, inherited germline variants in predisposition genes are more important than previously assumed for the pathogenesis of pediatric cancers.

scholarly journals Introduction of a New Pathology Workup Protocol for Glottic Cancer Treated With Transoral Laser Microsurgery (TLM): Prospective Analysis of Oncological Outcomes and Matched Case-Control Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Jeroen Meulemans ◽  
Sara Narimani ◽  
Esther Hauben ◽  
Sandra Nuyts ◽  
Annouschka Laenen ◽  
...  
Keyword(s):  
Case Control ◽  
Margin Status ◽  
Glottic Cancer ◽  
P Value ◽  
Control Analysis ◽  
Prognostic Effect ◽  
Oncological Outcomes ◽  
Deep Margin ◽  
Matched Case ◽  
Case Control Analysis

Background/PurposeThe value of margin status after TLM for glottic cancer is debatable, due to difficulties in specimen orientation and margin analysis. To reduce these difficulties, we recently introduced a standardized protocol of oriented fixation of TLM specimens. This proved feasible and resulted in high margin evaluability rates and a decreased rate of false positive deep margins, when compared to a historical TLM cohort. For the patients whose specimens were processed according to this protocol, we prospectively analyzed oncological outcomes, identified prognostic factors and assessed the influence of the protocol introduction on outcomes compared with a historical TLM cohort.MethodsNinety-six patients with glottic malignancies treated with TLM were included. Resection specimens were processed according to the new protocol. Descriptive statistics and survival analyses were used to determine oncological outcomes. To assess the effect of the protocol introduction on outcomes, a matched-case-control analysis was performed, using a historical TLM-cohort as controls. The Cox proportional hazards model was used to analyze prognostic effects of patient and treatment characteristics, including the pathology protocol introduction, on overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and local recurrence-free survival (LRFS).ResultsTwo-year outcomes were favorable: 88.5% OS, 97.0% DSS, and 87.6% LRFS. At multivariable analysis, the presence of multiple positive superficial margins was a negative prognosticator for OS (HR 4.102) and increasing cT classification proved a negative prognosticator for DFS (HR 2.828) and LRFS (HR 2.676). Matched case-control analysis did not reveal a significant difference in oncological outcomes between cohorts. Deep margin status had a strong differential effect for DFS (p-value for interaction = 0.0205) and for LRFS (p-value for interaction = 0.0176) between cohorts, indicating a prognostic effect of deep margin status on both outcomes in the current cohort, but not in the historical cohort.Discussion/ConclusionThe introduction of a new standardized technique of oriented fixation of TLM specimens did not affect oncological outcomes when compared to a historical TLM cohort, but assigned a significant prognostic effect to deep margin status for DFS and LRFS, facilitating the decision making process with regards to planning of second-look procedures, administration of adjuvant radiotherapy or determination of follow-up intensity.

scholarly journals Investigation of fever in the eastern borders of Kollam district, Kerala, India

2018 ◽  
Vol 5 (6) ◽  
pp. 2243
Author(s):  
Soumya Gopakumar ◽  
Sonia Scaria ◽  
Achu Thomas ◽  
Zinia T. Nujum ◽  
Devi Mohan
Keyword(s):  
The State ◽  
P Value ◽  
Control Analysis ◽  
Cross Sectional Survey ◽  
Chi Square ◽  
Cross Sectional ◽  
Breeding Sites ◽  
State Surveillance ◽  
Surveillance Report ◽  
Case Control Analysis

Background: The state of Kerala is endemic for Dengue. The district Kollam in Kerala reported increasing fever trend as per the state surveillance report. So an investigation was planned to estimate the burden of fever in the locality of reported Dengue cases, to calculate vector indices around areas of confirmed cases and to study the clinical profile and risk factors of Dengue fever.Methods: A Cross sectional survey with entomological survey was conducted in houses around the confirmed dengue cases. A case control analysis was done with Dengue positive as cases and negative test results among the fever cases as controls .Odds ratio was calculated for strength of association and statistical test of significance using Chi Square test.Results: Total number of households visited was 80, numbers of hospitalized patients were 26.Total fever cases studied were 46 of which 30.4% and 8.7% were positive for IgM and IgG Dengue respectively.PCR was positive in 28.3%. Chills [OR – 3.55 (1.05-12.1)], p value < 0.03, was found to be significantly associated with Dengue positivity .Dengue positivity was higher among housewives, but not found to be statistically significant. 51.2% of the households had water storage containers at home. Breteau index in one of the areas surveyed was 60 and 52.Conclusion: More awareness needed to be generated among the public of the importance of identifying and destroying the vector breeding sites around households as very often breeding sites are found right inside houses.   

scholarly journals Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice

2020 ◽  
Author(s):  
Stefan Russmann ◽  
Ali Rahmany ◽  
David Niedrig ◽  
Karl-Dietrich Hatz ◽  
Katja Ludin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Practice ◽  
Successful Implementation ◽  
Control Analysis ◽  
Loss Of Function ◽  
Increased Risk ◽  
Clopidogrel Therapy ◽  
Management Recommendations ◽  
Case Control Analysis ◽  
Ischemic Events

Abstract Purpose The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes. Methods We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis. Results Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3–14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies. Conclusion PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.

scholarly journals Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Li ◽  
Belle W. X. Lim ◽  
Ella R. Thompson ◽  
Simone McInerny ◽  
Magnus Zethoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Candidate Genes ◽  
Familial Aggregation ◽  
Loss Of Function ◽  
Cancer Data ◽  
Pathogenic Variants ◽  
New Genes ◽  
Predisposing Genes ◽  
Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

scholarly journals LINC01089 functions as a ceRNA for miR-152-3p to inhibit non‐small lung cancer progression through regulating PTEN

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huixian Zhang ◽  
Hao Zhang ◽  
Xingya Li ◽  
Siyuan Huang ◽  
Qianqian Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Expression Level ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Protein Coding ◽  
Tensin Homolog ◽  
Pten Mrna

Abstract Background Long non-coding RNAs (lncRNAs) have been reported to exert crucial functions in regulating the progression of human cancers. However, the function and mechanism of long intergenic non-protein coding RNA 01089 (LINC01089) in non-small cell lung cancer (NSCLC) have not been revealed. Methods The expression level of LINC01089, microRNA (miRNA, miR)-152-3p and phosphatase and tensin homolog deleted onc hromosome ten (PTEN) mRNA was detected by quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function models were established with NSCLC cell lines, the proliferation, migration and invasion of NSCLC cells were detected by cell counting kit-8 (CCK-8) assay, scratch healing assay, Transwell assay, respectively. Dual luciferase reporter assay was employed to validate the binding relationship between miR-152-3p and LINC01089 or the 3’UTR of PTEN. Western blot was used to detect PTEN expression in NSCLC cells after LINC01089 and miR-152-3p were selectively modulated. Results LINC01089 was down-regulated in NSCLC tissues and cells. Functional experiments showed that knockdown of LINC01089 could promote the proliferation, migration and invasion of NSCLC cells, while over-expression of LINC01089 had the opposite effects. miR-152-3p was identified as a functional target for LIN01089, and miR-152-3p could reverse the function of LINC01089. Additionally, LINC01089 could up-regulate the expression level of PTEN via repressing miR-152-3p. Conclusions Down-regulation of LINC01089 promoted the progression of NSCLC through regulating miR-152-3p/PTEN axis.

Relationships between attention to emotion and anxiety among a community sample of adolescents

2021 ◽  
pp. 1-12
Author(s):  
Benjamin C. Mullin ◽  
Jacob B. W. Holzman ◽  
Laura Pyle ◽  
Emmaly L. Perks ◽  
Yaswanth Chintaluru ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Eye Tracking ◽  
Attentional Bias ◽  
Community Sample ◽  
Full Range ◽  
Small Samples ◽  
Control Analysis ◽  
Attentional Processes ◽  
Anxious Youth ◽  
Case Control Analysis

Abstract Background Attentional bias to threat has been implicated as a cognitive mechanism in anxiety disorders for youth. Yet, prior studies documenting this bias have largely relied on a method with questionable reliability (i.e. dot-probe task) and small samples, few of which included adolescents. The current study sought to address such limitations by examining relations between anxiety – both clinically diagnosed and dimensionally rated – and attentional bias to threat. Methods The study included a community sample of adolescents and employed eye-tracking methodology intended to capture possible biases across the full range of both automatic (i.e. vigilance bias) and controlled attentional processes (i.e. avoidance bias, maintenance bias). We examined both dimensional anxiety (across the full sample; n = 215) and categorical anxiety in a subset case-control analysis (n = 100) as predictors of biases. Results Findings indicated that participants with an anxiety disorder oriented more slowly to angry faces than matched controls. Results did not suggest a greater likelihood of initial orienting to angry faces among our participants with anxiety disorders or those with higher dimensional ratings of anxiety. Greater anxiety severity was associated with greater dwell time to neutral faces. Conclusions This is the largest study to date examining eye-tracking metrics of attention to threat among healthy and anxious youth. Findings did not support the notion that anxiety is characterized by heightened vigilance or avoidance/maintenance of attention to threat. All effects detected were extremely small. Links between attention to threat and anxiety among adolescents may be subtle and highly dependent on experimental task dimensions.

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