scholarly journals Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Satoshi Kawakami ◽  
Shinichi Takano ◽  
Mitsuharu Fukasawa ◽  
Hiroko Shindo ◽  
Ei Takahashi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gallbladder Carcinoma ◽  
Clinical Information ◽  
Pancreaticobiliary Maljunction ◽  
Control Group ◽  
Genetic Changes ◽  
Next Generation Sequencing Ngs ◽  
Laser Capture ◽  
Generation Sequencing ◽  
Gene Alterations

Abstract Background The genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS). Methods We retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status. Results The most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p <  0.01). Conclusions TP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

scholarly journals Differential Gene Expression in Patients With Prostate Cancer and in Patients With Parkinson Disease: an Example of Inverse Comorbidity

2021 ◽  
Author(s):  
Pietro Pepe ◽  
Simona Vetrano ◽  
Rossella Cannarella ◽  
Aldo E Calogero ◽  
Giovanna Marchese ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Causes Of Death ◽  
Genetic Factors ◽  
Target Genes ◽  
Lewy Bodies ◽  
Control Group ◽  
Healthy Donors ◽  
Differential Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies (LBs) and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named “inverse comorbidity”. The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. In the present study, next-generation sequencing (NGS) transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

scholarly journals Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sheila Castro-Sánchez ◽  
Paula Suarez-Bregua ◽  
Rossina Novas ◽  
María Álvarez-Satta ◽  
Jose L. Badano ◽  
...  
Keyword(s):  
Wild Type ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Genetic Changes ◽  
Bardet Biedl Syndrome ◽  
Main Challenge ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Human Wild Type

Abstract The multiple genetic approaches available for molecular diagnosis of human diseases have made possible to identify an increasing number of pathogenic genetic changes, particularly with the advent of next generation sequencing (NGS) technologies. However, the main challenge lies in the interpretation of their functional impact, which has resulted in the widespread use of animal models. We describe here the functional modelling of seven BBS loci variants, most of them novel, in zebrafish embryos to validate their in silico prediction of pathogenicity. We show that target knockdown (KD) of known BBS (BBS1, BB5 or BBS6) loci leads to developmental defects commonly associated with ciliopathies, as previously described. These KD pleiotropic phenotypes were rescued by co-injecting human wild type (WT) loci sequence but not with the equivalent mutated mRNAs, providing evidence of the pathogenic effect of these BBS changes. Furthermore, direct assessment of cilia located in Kupffer’s vesicle (KV) showed a reduction of ciliary length associated with all the studied variants, thus confirming a deleterious effect. Taken together, our results seem to prove the pathogenicity of the already classified and unclassified new BBS variants, as well as highlight the usefulness of zebrafish as an animal model for in vivo assays in human ciliopathies.

scholarly journals PATH-09. NEXT-GENERATION SEQUENCING OF GLIOBLASTOMA MULTIFORME ‘EXTREME RESPONDERS’

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii165-ii165
Author(s):  
Mohammed Zameer ◽  
Cassie Fives ◽  
Niamh Peters ◽  
Niamh Birmingham ◽  
Dearbhaile Collins ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Glioblastoma Multiforme ◽  
Methylation Status ◽  
Idh1 Mutation ◽  
Adjuvant Chemoradiotherapy ◽  
Control Group ◽  
Next Generation ◽  
Extreme Response ◽  
Generation Sequencing ◽  
Gene Alterations

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is the most common primary brain among adults. Despite steady advances in treatment, the outcome remains universally lethal. Median overall survival in a population-based study is approximately 10 to 12 months. Prognostic factors in GBM patients include age, performance score, extent of surgical resection, IDH1 mutation status and MGMT methylation status. Survival &gt; 2 years is rare; for the purpose of this study we have defined these patients ‘extreme responders.’ This study aims to identify genomic signatures and gene alterations that may have contributed to ‘extreme response’ to standard adjuvant chemoradiotherapy. METHODS A total of 12 out of 141 primary GBM patients were identified as ‘extreme responders’ as part of a retrospective chart review between 2005 - 2016. Of the 12 suitable for NGS testing, 9 were analyzed using the Foundation One CDx® (next-generation sequencing platform) which interrogates 324 genes, microsatellite status and tumour mutational burden (TMB). Baseline demographics, clinical characteristics, and NGS results were compared. RESULTS Of the 9 patients tested, over half were female (5, 55%) and median age at diagnosis was 53 years. Gross total resection was performed at diagnosis in 3 cases. MGMT status was available for 5 patients and was methylated in 3. NGS results revealed: MSI stable in all patients, median TMB 3 muts/Mb and most common gene alterations were TP53 (5/9); ATRX (4/9); EGFR (3/9); CDKN2A/B (3/9); IDH1(3/9); PIK3R1(3/9) and PTEN (3/9). CONCLUSION Acknowledging the fact that our sample size was small and no control group was tested, our study infers a higher incidence of IDH1, TP53 and ATRX mutations which are more common in secondary glioblastomas and this may be a contributing factor towards longer survival in our cohort. We did not identify any universal molecular marker predictive of improved prognosis or exquisite sensitivity to chemoradiotherapy.

scholarly journals Pulmonary microbiome patterns correlate with the course of the disease in patients with sepsis-induced ARDS

2019 ◽  
Author(s):  
Felix Carl Fabian Schmitt ◽  
Anna Lipinski ◽  
Stefan Hofer ◽  
Florian Uhle ◽  
Christian Nusshag ◽  
...  
Keyword(s):  
Distress Syndrome ◽  
Diversity Index ◽  
Diagnostic Methods ◽  
Control Group ◽  
P Value ◽  
Pathogen Identification ◽  
Epithelial Lining Fluid ◽  
Α Diversity ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS) are hallmarked by high mortality rates. An early and goal directed antibiotic therapy is crucial for patients’ survival. The clinical use of a Next Generation Sequencing (NGS)-based approach for pathogen identification might lead to an improved diagnostic performance. Therefore, the objective of this study was to examine changes in the pulmonary microbiome and resulting influences on patients’ outcome in septic ARDS, but also to compare NGS- and culture-based diagnostic methods for pathogen identification.Results In total, 30 patients in two groups were enrolled in the study: (1) 15 septic ARDS patients and (2) 15 patients undergoing oesophageal resection serving as controls. In the ARDS group, blood samples were collected at ARDS onset as well as 5 days and 10 days afterwards. At the same timepoints, bronchoalveolar lavages (BAL) were performed to collect epithelial lining fluid for culture-, as well as NGS-based analyses and to evaluate longitudinal changes in the pulmonary microbiome. In the control group, only one BAL and one blood sample were collected immediately prior to the surgical procedure. ARDS patients showed a significantly decreased α-diversity (p=0.003**) and an increased dominance (p=0.005**) in their pulmonary microbiome. The α-diversity index revealed a good correlation with the length of stay in the intensive care unit (ICU) (p-value=0.027) and the need for mechanical ventilation (p-value=0.027). In 42.9% of all ARDS patients, culture-based results were not concordant with NGS-based findings. Moreover, culture-based results remained negative in 5 cases where NGS-based diagnostics revealed signs of bacterial colonisation.Conclusion Sepsis-induced ARDS is associated with a significant dysbiosis of patients’ pulmonary microbiome, which is closely correlated with the clinical course of the disease. Furthermore, an NGS-based diagnostic approach was shown to be promising for pathogen identification in septic ARDS.

scholarly journals Applying Precision Medicine in Clinical Practice

2020 ◽  
Vol 95 (6) ◽  
pp. 382-386
Author(s):  
Kyu-pyo Kim
Keyword(s):  
Clinical Practice ◽  
Precision Medicine ◽  
Clinical Care ◽  
Clinical Information ◽  
Data Systems ◽  
Data Collection And Analysis ◽  
Clinical Records ◽  
Next Generation Sequencing Ngs ◽  
Modern Era ◽  
Generation Sequencing

Precision medicine is the modern era version of “personalized medicine”, which integrates data from genomics and clinical information to optimize the care delivered to patients. As next generation sequencing (NGS) revolutionized the speed and cost of genomic sequencing, precision medicine entered clinical practice in 2017 via the national reimbursement of oncology and rare diseases. In parallel, the digitalization of clinical data through electronic health recording (EHR) and hospital information systems has allowed data collection and analysis. This has led to the integration of biomarkers and clinical records, which have introduced precision medicine into clinical practice. Today, many countries and medical institutes are endeavoring to create systems that will enable precision medicine to be applied to clinical practice. These data systems will benefit the patient by providing accurate data based on his/her characteristics rather than the conventional approach of using “average data”. Internal medicine will transform into a data-driven science that enables physicians to translate molecular biomarkers and big data analysis into improved clinical care.

Plasma next-generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICIs): Impact of STK11 and TP53 mutations on outcome.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3046-3046
Author(s):  
Alberto Pavan ◽  
Elisabetta Zulato ◽  
Lorenzo Calvetti ◽  
Alessandra Ferro ◽  
Giorgia Nardo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Predictive Markers ◽  
Control Group ◽  
Tp53 Mutations ◽  
Multiple Tumor ◽  
Promising Tool ◽  
Next Generation Sequencing Ngs ◽  
The Impact ◽  
Generation Sequencing

3046 Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.

scholarly journals Mutation analysis of a 10-gene panel for colorectal cancer in Huizhou, Guangdong Province of China

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110610
Author(s):  
Jun Li ◽  
Aihua Sun ◽  
Guofang Zhong ◽  
Ying He ◽  
Hailin Xiong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Gene ◽  
Gene Mutations ◽  
Clinical Information ◽  
Comprehensive Analysis ◽  
Gene Panel ◽  
Targeting Therapy ◽  
Three Samples ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Objective This study aimed to investigate the type and frequency of mutations in 10 genes in 85 colorectal cancer (CRC) patients in Huizhou and the guiding significance of targeted drug use. Methods The 10-gene panel next-generation sequencing (NGS) was used to assess genetic variants in 85 CRC patients from the Huizhou area combined with clinical information for a comprehensive analysis. Results Upon initial mutation testing, 68% (58/85) were positive. The mutation frequencies of these genes, including KRAS, PIK3CA, NRAS, ERBB2, BRAF, EGFR, and PDGFRA, were 51%, 20%, 5%, 4%, 4%, 1%, and 1%, respectively. Overall, 29 mutation types were detected from seven genes. More mutations were detected in more advanced cancers. There were three samples with multiple mutations of a single gene, including KRAS (n = 2) and ERBB2 (n = 2), 12 samples with multiple mutations of double genes, including KRAS/PIK3CA (n = 10), BRAF/PIK3CA (n = 1), and NRAS/PIK3CA (n = 1), and one sample with multiple mutations of three genes, including ERBB2/KRAS/PIK3CA (n = 1). Theoretically, 27 patients could receive targeted treatment. During the actual treatment, 10 patients received bevacizumab, cetuximab, or fruquintinib with no progression ranging from 12 to 24 months. Conclusion Gene mutations detected by a 10-gene panel were useful for targeting therapy of CRC in Huizhou.

scholarly journals Prevalence of Thalassemia-carrier of Couples at Childbearing Age and Risk Prediction of Thalassemia

2021 ◽  
Author(s):  
Liu-song Wu ◽  
Li-Jun Zhang ◽  
Hong-Fang Luo ◽  
Ge Huang ◽  
Xi Luo ◽  
...  
Keyword(s):  
Globin Gene ◽  
Accurate Method ◽  
Childbearing Age ◽  
Hematologic Disease ◽  
Gene Carriers ◽  
Next Generation Sequencing Ngs ◽  
Epidemiological Characteristics ◽  
Generation Sequencing ◽  
Gene Alterations ◽  
Hematological Tests

Abstract Background: Thalassemia is highly prevalent hematologic disease in Guizhou, China. This study aims to determine the epidemiological characteristics of thalassemia for couples at childbearing age in this subpopulation.Results: There were 4481 couples at childbearing age recruited for thalassemia-carrier screening through both traditional hematological tests and next-generation sequencing (NGS). Of them, 1314 (14.66%) thalassemia-carriers were identified, including 857 (9.76%) α-thalassemia, 391 (4.36%) β-thalassemia, and 48 (0.54%) composite α and β-thalassemia. Of them, 38 couples were high-risk thalassemia carriers. In addition, 12 a-globin gene alterations and 16 b-globin mutations were detected including four novel thalassemia mutations. SEA is the most common α-thalassemia genotype (26.86%), CD41-42 is the most prevalent β-thalassemia genotype (36.57%); the αα/-α3.7 + CD41-42 is the most frequent composite α and β-thalassemia genotype (18.75%). Ethnically, the Zhuang has the highest rate of thalassemia-gene carriers among the ethnic groups. Geographically, Qiannan presented the highest rate of thalassemia-gene carrier. Conclusion: This result enriched the genetic map of thalassemia and provided thalassemia genetic counseling and fertility-guidance for thalassemia-carriers in Guizhou, China. The NGS is so far the most accurate method for population thalassemia screening.

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