scholarly journals CDH1 and CTNNA1 Genetic Screening in Tunisian Patients with Hereditary Diffuse Gastric Carcinoma

2021 ◽  
Author(s):  
Jihenne BEN AISSA-HAJ ◽  
Maria Kabbage ◽  
Houcemeddine Othmen ◽  
Patrick Saulnier ◽  
Azer Ferah ◽  
...  
Keyword(s):  
High Risk ◽  
Sanger Sequencing ◽  
Protein Complexes ◽  
Personalised Medicine ◽  
Large Deletion ◽  
Conformational Space ◽  
Diffuse Gastric Cancer ◽  
Large Rearrangement ◽  
Pathogenic Variants ◽  
The Status

Abstract Background: Mutational screening of the CDH1 gene is a standard treatment for patients who meet the criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of this study was to identify CDH1 as well as CTNNA1 mutation profiles predisposing to HDGC from Tunisia. Methods: Thirty four cases were included for this purpose with a mean age at diagnosis of 48 years old. We performed Sanger Sequencing for the entire coding sequence of both genes and MLPA (Multiplex Ligation Probe Amplification) assay to investigate large rearrangements of the CDH1 gene. Results: As a result, three cases (8.82%) carried probably pathogenic variants in the CDH1 gene. These variants involves a novel splice alteration, a missense located in exon 14 detected by Sanger Sequencing and a large rearrangement detected by MLPA assay.Conclusion: Our results suggest that the CDH1 p.G761R variant is probably pathogenic and involved in the conformational space shift of the protein. Molecular modeling analysis highlights a putative influence on the conformational properties of the Juxta-Membrane Domain core (JMD) that could result in destabilizing the protein-protein complexes and therefore impacting the downstream pathways. Also, a large deletion from the 5' locus including exons 1 and 2 of the CDH1 gene implicating the signal peptide and a part of the precursor domain of the protein. These findings highlight the critical importance of screening for large CDH1 rearrangements as well as mutations for the management of HDGC families and individuals at high risk for more personalised medicine. We therefore suggest a revision of the status of p.G761R mutation from Variant of Unknown Significance (VUS) to likely pathogenic.

Co-occurrence of germline BRCA1 and CDH1 pathogenic variants

2020 ◽  
pp. jmedgenet-2020-106972
Author(s):  
Marie-Charlotte Villy ◽  
Emmanuelle Mouret-Fourme ◽  
Lisa Golmard ◽  
Véronique Becette ◽  
Nasrine Callet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Counselling ◽  
Familial Breast Cancer ◽  
Large Deletion ◽  
Diffuse Gastric Cancer ◽  
Complex Situation ◽  
Pathogenic Variants ◽  
History Of ◽  
Paternal Grandmother

Introduction: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion: This complex situation is challenging for genetic counselling and management of at-risk individuals.

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 Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Screening ◽  
Sanger Sequencing ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants ◽  
Case Summary ◽  
Heterozygous Carriers ◽  
Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

scholarly journals Moving out of town? The status of alien plants in high‐Arctic Svalbard, and a method for monitoring of alien flora in high‐risk, polar environments

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Jesamine C. Bartlett ◽  
Kristine Bakke‐Westergaard ◽  
Ingrid M. G. Paulsen ◽  
Ronja E. M. Wedegärtner ◽  
Florian Wilken ◽  
...  
Keyword(s):  
High Risk ◽  
High Arctic ◽  
Alien Plants ◽  
Alien Flora ◽  
The Status

scholarly journals The Ultra-High-Risk for psychosis groups: Evidence to maintain the status quo

2018 ◽  
Vol 195 ◽  
pp. 543-548 ◽  
Author(s):  
M.J. McHugh ◽  
P.D. McGorry ◽  
H.P. Yuen ◽  
I.B. Hickie ◽  
A. Thompson ◽  
...  
Keyword(s):  
High Risk ◽  
Status Quo ◽  
The Status ◽  
Ultra High Risk

P–548 High-risk genetic matching on gamete donors: complete genes analysis or genotyping test?

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Molin. Romero ◽  
A Yoldi ◽  
M Gañán ◽  
P Navas ◽  
J L De. Pico ◽  
...  
Keyword(s):  
High Risk ◽  
Ethnic Origin ◽  
Carrier Screening ◽  
Reproductive Risk ◽  
Pathogenic Variants ◽  
Genetic Matching ◽  
Registration Number ◽  
Oocyte Donors ◽  
Legislative Measures

Abstract Study question What carrier screening test is better to reduce the risk of offspring being affected by recessive diseases when genetic matching is performed with gamete donors: complete or targeted genes analysis? Summary answer The use of complete genes analysis in the carrier screening of gamete donors reduces the risk of offspring being affected by recessive diseases. What is known already Legislative measures and scientific societies alike call for more research to be conducted into recessive diseases in gamete donors, in order to reduce reproductive risk. However, it is still unclear which genes should be studied and what type of data analysis, targeted or nontargeted, should be performed. Study design, size, duration This descriptive observational study of 923 oocyte donors and 895 semen donors was conducted from January 2017 to August 2020, at a private gamete bank. Participants/materials, setting, methods 1818 gamete donors screened by NGS and nontargeted analysis of the variants, the pathogenic variants detected were analysed to estimate the probability of high-risk genetic matching and to determine the results that would have been obtained if the three most commonly used genotyping tests for carriers of recessive diseases in ART had been applied. Main results and the role of chance The probability of high-risk genetic matching with gamete donation, screened by NGS and complete genes analysis, was 5.48%, versus the 0.57–2.8% that would have been obtained if the genotyping test had been applied. Of the 1739 total variants found, only 28.69% would have been detected by all three targeted tests considered and 45.66% of the variants would not have been detected by any of them. Limitations, reasons for caution The study was not based in the general population, was limited to a population of Mediterranean ethnic origin. In addition, our study only analysed 302 recessive diseases of the 1,300 plus that have been described. Wider implications of the findings: Our study highlights the considerable heterogeneity of the genotyping tests commonly used in ART, which present significant differences in their ability to detect pathogenic variants. Therefore, the use of genotyping tests for genetic matching is associated with a higher reproductive risk, compared to the use of complete genes analysis. Trial registration number Not applicable

scholarly journals The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

2019 ◽  
Vol 144 (11) ◽  
pp. 2683-2694 ◽  
Author(s):  
Stephanie Schubert ◽  
Jana L. Luttikhuizen ◽  
Bernd Auber ◽  
Gunnar Schmidt ◽  
Winfried Hofmann ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
High Frequency ◽  
Pathogenic Variants

scholarly journals Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 374
Author(s):  
Simon Bailey ◽  
Nicolas André ◽  
Lorenza Gandola ◽  
Maura Massimino ◽  
Stefan Rutkowski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Disease Risk ◽  
Risk Groups ◽  
Randomised Clinical Trial ◽  
Paediatric Oncology ◽  
High Dose ◽  
The Status ◽  
Risk Patients

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

scholarly journals Gene Panel Sequencing in a Chinese High-risk Breast Cancer Cohort

2019 ◽  
Author(s):  
Xianyu Zhang ◽  
Xiaohong Wang ◽  
Bingbing Song ◽  
Kang Shao ◽  
Guibo Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Gene Sequencing ◽  
Multiple Gene ◽  
Brca Gene ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
High Risk Breast Cancer ◽  
High Risk Breast ◽  
Risk Breast Cancer

AbstractCurrently, over 20 genes have been defined that can confer susceptibility for high-risk breast cancer. Although research has proved the utility of multiple-gene sequencing in the assessment of breast cancer risk, there is little data from China patients. Here, we use a multiple-gene sequencing panel to identify the variant spectrum in Chinese high-risk breast cancer subjects.A total of 829 Chinese high-risk breast cancer patients participated in the research. The coding regions of 115 hereditary cancer susceptibility genes were sequenced using a next generation sequencing platform. In total, 193 pathogenic variants were identified in 45 genes from 177 patients. The pathogenic variant carrier rate is 21.4%: with 10.5% patients carrying a BRCA1 or BRCA2 mutation only, 10.0% of patients carried non-BRCA gene mutations only, while 1.0% of patients carried both a BRCA1/2 and a non-BRCA gene mutation. Variants of uncertain significance (VUS) totaling 2632 were identified in 115 genes from 787 of 829 patients: 82.5% patients carried more than one VUS, and only 5.1% patients did not carry any VUS. Families carrying pathogenic variants were tracked and adenoma was founded in three of them. Our data provide a comprehensive analysis of potential susceptibility variations of high-risk for breast cancer in a Chinese population. This data will be useful for the comparison of the susceptibility variation spectrum between different populations and to discover potential pathogenic variants to improve the prevention and treatment of high-risk breast cancer.

scholarly journals The Spread of COVID-19 in Nigeria: The Influence of Transportation and Economic Zones

2021 ◽  
pp. 27-35
Author(s):  
Nathaniel O. Ajayi ◽  
Richard O. Awonusika ◽  
Adeniyi S. Ale ◽  
Ayooluwade Ebiwonjumi
Keyword(s):  
High Risk ◽  
Large Scale ◽  
National Policy ◽  
Human Movement ◽  
Health Crisis ◽  
Spatial Spread ◽  
The Status ◽  
The Government ◽  
Novel Coronavirus ◽  
Economic Zones

The novel coronavirus (2019-nCoV) now known as Covid-19 was first detected in the city of Wuhan, China in December 2019. The disease rapidly spread to other cities in China and to other parts of the world. The aim of this study is to investigate the contribution which the economic zones and movement of people into the country and from city to city and State to State within the country have on the spread of the disease in Nigeria. Data of the daily update of Covid-19 occurrence in Nigeria as given by the NCDC Covid-19 Situation report were assembled. The data of the first index in each State between February 27 and March 28, 2020 with the status of whether they were from foreign travel or from within the community was compiled. The results show that economic zones and human movement contribute to the early spread of the disease. The initial spatial spread in Nigeria was observed to follow closely behind the test laboratory distribution pattern. This may suggest that samples from the locations far from the laboratories were not obtained, hence the suggestion for early aggressive country-wide-large scale testing to cover almost everyone should be started very early before the spread is everywhere. The test labs should cover the whole country with the tests made free and mandatory to encourage and force people to come out for it and the restriction protocols should strictly be adhered to. The boarders of the country should be closed early to stop further import of the disease from the high risk countries. When the airports are later re-opened, they should not be to the high-risk countries of the disease. There is also a need for a national policy on responding to and managing any future public health crisis such as Covid-19 pandemic before its occurrence. This policy will help the government to know what to start doing quickly when there is any occurrence. Government should also look inward to mobilize the scientists inside the country by providing research grants purposely to combat the pandemic. Such grants will enable our scientists to make their contribution in addition to the ones made by the scientists outside the country.

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