scholarly journals Fanconi Anaemia, Childhood Cancer and the BRCA Genes

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1520
Author(s):  
Emma R. Woodward ◽  
Stefan Meyer
Keyword(s):  
Childhood Cancer ◽  
Cancer Predisposition ◽  
Fanconi Anaemia ◽  
Childhood Cancers ◽  
Developmental Abnormalities ◽  
Epithelial Cancers ◽  
Childhood Malignancies ◽  
Pathogenic Variants ◽  
Genetic Features

Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.

Genetic Predisposition to Childhood Cancer in the Genomic Era

2019 ◽  
Vol 20 (1) ◽  
pp. 241-263 ◽  
Author(s):  
Sharon E. Plon ◽  
Philip J. Lupo
Keyword(s):  
Childhood Cancer ◽  
Pediatric Cancer ◽  
Association Studies ◽  
Cancer Predisposition ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Pathogenic Variants ◽  
Pediatric Cancer Patients ◽  
Genes Encoding ◽  
Genome Analyses

Developments over the past five years have significantly advanced our ability to use genome-scale analyses—including high-density genotyping, transcriptome sequencing, exome sequencing, and genome sequencing—to identify the genetic basis of childhood cancer. This article reviews several key results from an expanding number of genomic studies of pediatric cancer: ( a) Histopathologic subtypes of cancers can be associated with a high incidence of germline predisposition, ( b) neurodevelopmental disorders or highly penetrant cancer predisposition syndromes can result from specific patterns of variation in genes encoding the SMARC family of chromatin remodelers, ( c) genome-wide association studies with relatively small pediatric cancer cohorts have successfully identified single-nucleotide polymorphisms with large effect sizes and provided insight into population differences in cancer risk, and ( d) multiple exome or genome analyses of unselected childhood cancer cohorts have yielded a 7–10% incidence of pathogenic variants in cancer predisposition genes. This work supports the increasing use of genomic sequencing in the care of pediatric cancer patients and at-risk family members.

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

scholarly journals Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

2021 ◽  
Author(s):  
Anna Byrjalsen ◽  
Illja J. Diets ◽  
Jette Bakhuizen ◽  
Thomas van Overeem Hansen ◽  
Kjeld Schmiegelow ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Pediatric Cancer ◽  
Causal Relation ◽  
Evaluation Criteria ◽  
Cancer Predisposition ◽  
Gene Panel ◽  
Childhood Onset ◽  
Children With Cancer ◽  
Cancer Predisposition Syndrome ◽  
A Prospective Study

AbstractIncreasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First Century

2010 ◽  
Vol 28 (15) ◽  
pp. 2625-2634 ◽  
Author(s):  
Malcolm A. Smith ◽  
Nita L. Seibel ◽  
Sean F. Altekruse ◽  
Lynn A.G. Ries ◽  
Danielle L. Melbert ◽  
...  
Keyword(s):  
United States ◽  
Childhood Cancer ◽  
Cancer Mortality ◽  
Lymphoblastic Leukemia ◽  
The United States ◽  
Mortality Rates ◽  
Mortality Data ◽  
Childhood Cancers ◽  
Essential Information ◽  
The Impact

Purpose This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research directions. Methods Incidence and survival data for childhood cancers came from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries, and mortality data were based on deaths in the United States that were reported by states to the Centers for Disease Control and Prevention by underlying cause. Results Childhood cancer incidence rates increased significantly from 1975 through 2006, with increasing rates for acute lymphoblastic leukemia being most notable. Childhood cancer mortality rates declined by more than 50% between 1975 and 2006. For leukemias and lymphomas, significantly decreasing mortality rates were observed throughout the 32-year period, though the rate of decline slowed somewhat after 1998. For remaining childhood cancers, significantly decreasing mortality rates were observed from 1975 to 1996, with stable rates from 1996 through 2006. Increased survival rates were observed for all categories of childhood cancers studied, with the extent and temporal pace of the increases varying by diagnosis. Conclusion When 1975 age-specific death rates for children are used as a baseline, approximately 38,000 childhood malignant cancer deaths were averted in the United States from 1975 through 2006 as a result of more effective treatments identified and applied during this period. Continued success in reducing childhood cancer mortality will require new treatment paradigms building on an increased understanding of the molecular processes that promote growth and survival of specific childhood cancers.

scholarly journals Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 116
Author(s):  
Francisco Perez-Dominguez ◽  
Diego Carrillo-Beltrán ◽  
Rancés Blanco ◽  
Juan P. Muñoz ◽  
Grettell León-Cruz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Development ◽  
Biological Factors ◽  
Epithelial Cancers ◽  
Physical Chemical ◽  
Sensor Protein ◽  
Cupin Superfamily ◽  
Functionally Diverse ◽  
Light Chain Enhancer

Pirin is an oxidative stress (OS) sensor belonging to the functionally diverse cupin superfamily of proteins. Pirin is a suggested quercetinase and transcriptional activator of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Its biological role in cancer development remains a novel area of study. This review presents accumulating evidence on the contribution of Pirin in epithelial cancers, involved signaling pathways, and as a suggested therapeutic target. Finally, we propose a model in which Pirin is upregulated by physical, chemical or biological factors involved in OS and cancer development.

scholarly journals Interaction of the Tobacco Mosaic Virus Replicase Protein with the Aux/IAA Protein PAP1/IAA26 Is Associated with Disease Development

2005 ◽  
Vol 79 (4) ◽  
pp. 2549-2558 ◽  
Author(s):  
Meenu S. Padmanabhan ◽  
Sameer P. Goregaoker ◽  
Sheetal Golem ◽  
Haiymanot Shiferaw ◽  
James N. Culver
Keyword(s):  
Tobacco Mosaic Virus ◽  
Mosaic Virus ◽  
Protein S ◽  
Helicase Domain ◽  
Auxin Response ◽  
Disease Symptoms ◽  
Developmental Abnormalities ◽  
Replicase Protein ◽  
Transcriptional Alterations

ABSTRACT Virus-infected plants often display developmental abnormalities that include stunting, leaf curling, and the loss of apical dominance. In this study, the helicase domain of the Tobacco mosaic virus (TMV) 126- and/or 183-kDa replicase protein(s) was found to interact with the Arabidopsis Aux/IAA protein PAP1 (also named IAA26), a putative regulator of auxin response genes involved in plant development. To investigate the role of this interaction in the display of symptoms, a TMV mutant defective in the PAP1 interaction was identified. This mutant replicated and moved normally in Arabidopsis but induced attenuated developmental symptoms. Additionally, transgenic plants in which the accumulation of PAP1 mRNA was silenced exhibit symptoms like those of virus-infected plants. In uninfected tissues, ectopically expressed PAP1 accumulated and localized to the nucleus. However, in TMV-infected tissues, PAP1 failed to accumulate to significant levels and did not localize to the nucleus, suggesting that interaction with the TMV replicase protein disrupts PAP1 localization. The consequences of this interaction would affect PAP1's putative function as a transcriptional regulator of auxin response genes. This is supported by gene expression data indicating that ∼30% of the Arabidopsis genes displaying transcriptional alterations in response to TMV contain multiple auxin response promoter elements. Combined, these data indicate that the TMV replicase protein interferes with the plant's auxin response system to induce specific disease symptoms.

Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

2021 ◽  
pp. 26-35
Author(s):  
М.Д. Орлова ◽  
П. Гундорова ◽  
А.В. Поляков
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Genetic Diagnostics ◽  
Bardet Biedl Syndrome ◽  
Pathogenic Variants ◽  
Development Delay ◽  
Molecular Genetic Diagnostics ◽  
First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

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

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