scholarly journals Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ianthe A. E. M. van Belzen ◽  
Alexander Schönhuth ◽  
Patrick Kemmeren ◽  
Jayne Y. Hehir-Kwa
Keyword(s):  
Intratumor Heterogeneity ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Full Spectrum ◽  
Single Nucleotide ◽  
Sequencing Technologies ◽  
Cancer Genomes ◽  
Genomic Aberrations

AbstractCancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection. Biological and computational challenges confound SV detection in cancer samples, including intratumor heterogeneity, polyploidy, and distinguishing tumor-specific SVs from germline and somatic variants present in healthy cells. Classification of tumor-specific SVs is challenging due to inconsistencies in detected breakpoints, derived variant types and biological complexity of some rearrangements. Full-spectrum SV detection with high recall and precision requires integration of multiple algorithms and sequencing technologies to rescue variants that are difficult to resolve through individual methods. Here, we explore current strategies for integrating SV callsets and to enable the use of tumor-specific SVs in precision oncology.

Genetics of Schizophrenia and Bipolar Disorder

2017 ◽  
Author(s):  
Alexander Charney ◽  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

scholarly journals Integration of single nucleotide variants and whole-genome DNA methylation profiles for classification of rheumatoid arthritis cases from controls

Heredity ◽  
2020 ◽  
Vol 124 (5) ◽  
pp. 658-674 ◽  
Author(s):  
Mahmoud Amiri Roudbar ◽  
Mohammad Reza Mohammadabadi ◽  
Ahmad Ayatollahi Mehrgardi ◽  
Rostam Abdollahi-Arpanahi ◽  
Mehdi Momen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Single Nucleotide

scholarly journals 2466. What’s Lurking in the Drain? Serial transmission of NDM-1Klebsiella pneumoniae to patients admitted 9 months apart to the same ICU room

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S854-S854
Author(s):  
Becky A Smith ◽  
Amy Mathers ◽  
Shireen Kotay ◽  
Hardik Parikh ◽  
Katie E Barry ◽  
...  
Keyword(s):  
Environmental Samples ◽  
Index Patient ◽  
Point Prevalence ◽  
Secondary Case ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Environmental Investigation ◽  
Long Duration ◽  
Rectal Colonization

Abstract Background We evaluated the role of an in-room sink in NDM-1 K. pneumoniae (NDMKP) transmission. Methods In October 2017, Infection Prevention (IP) initiated weekly point prevalence rectal screening cultures in 4 ICUs. In 3/2018, IP launched an epidemiologic and environmental investigation following identification of a patient with NDMKP rectal colonization. Environmental samples including swabs of biofilm from drains and water from p-traps were obtained from the in-room sink. Illumina whole-genome sequencing (WGS) was performed on all NDMKP patient and environmental isolates. Single nucleotide variants (SNVs) were identified against the reference Klebsiella pneumoniae strain MLST15 (NZ_CP022127), and isolates within 150 SNVs of each other were considered to be genomically related. Results Two patients were identified with NDMKP infection or colonization between July 2017 and March 2018. The index patient had prolonged hospitalization and developed NDMKP bacteremia on hospital day (HD) 30. Approximately 9 months later, the second patient was admitted to the same ICU room that had been occupied by the index patient for 13 days and was identified to have NDMKP rectal colonization on HD 5. Environmental samples from the in-room sink of the ICU room grew NDMKP. WGS demonstrated relatedness between NDMKP isolates from the 2 patients (112 SNV), the index patient and the sink (52 SNV), and the second patient and the sink (80 SNV). The in-room sink was replaced in 4/18 and no further cases of NDMKP infection or colonization have been identified at DUH in over 12 months. Conclusion We report an NDM-1 K. pneumoniae transmission event possibly related to a contaminated in-room sink drain. Remarkably, 9 months elapsed between the index case and the second case, with no additional interim cases detected on weekly point-prevalence screening or clinical cultures. The long duration of time between and the index patient, secondary case, and sink culture may explain why WGS showed relatedness but not identical clones. Education around sink use, design, and more effective cleaning strategies are needed to mitigate environment-to-patient transmission of CRO. Disclosures All authors: No reported disclosures.

scholarly journals The role of single-nucleotide variants of the energy metabolism-linked genes SIRT3, PPARGC1A and APOE in amyotrophic lateral sclerosis risk

2016 ◽  
Vol 91 (6) ◽  
pp. 301-309 ◽  
Author(s):  
Diego Albani ◽  
Elisabetta Pupillo ◽  
Elisa Bianchi ◽  
Armando Chierchia ◽  
Rosalba Martines ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Energy Metabolism ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Lateral Sclerosis

scholarly journals Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

2019 ◽  
Author(s):  
Bing He ◽  
Peng Gao ◽  
Yang-Yang Ding ◽  
Chia-Hui Chen ◽  
Gregory Chen ◽  
...  
Keyword(s):  
Joint Analysis ◽  
General Strategy ◽  
Expression Data ◽  
Full Spectrum ◽  
Computational Framework ◽  
Small Indels ◽  
Pediatric Cancers ◽  
Cancer Genomes ◽  
Regulatory Landscape

AbstractInterpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here we developed a computational framework to identify risk noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as candidate risk mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation signatures can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

scholarly journals Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

2020 ◽  
Vol 6 (30) ◽  
pp. eaba3064
Author(s):  
Bing He ◽  
Peng Gao ◽  
Yang-Yang Ding ◽  
Chia-Hui Chen ◽  
Gregory Chen ◽  
...  
Keyword(s):  
Joint Analysis ◽  
General Strategy ◽  
Expression Data ◽  
Full Spectrum ◽  
Computational Framework ◽  
Small Indels ◽  
Pediatric Cancers ◽  
Cancer Genomes ◽  
Regulatory Landscape

Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here, we developed a computational framework to identify putative causal noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as putative causal mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation profiles can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

scholarly journals Application of Genomics to Clinical Practice in Haematological Malignancy

2019 ◽  
Vol 7 (4) ◽  
pp. 236-252
Author(s):  
Coen Veenstra ◽  
David Bruce ◽  
Adele Timbs ◽  
Angela Hamblin
Keyword(s):  
Bone Marrow Aspirate ◽  
Residual Disease ◽  
Clinical Care ◽  
Lymphoid Tissues ◽  
Haematological Malignancies ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Disease Entities

Abstract Purpose of Review The usual abundance of fresh cells and high-quality DNA derived from bone marrow aspirate and peripheral blood mean haematological malignancies are at the forefront of the application of genomics to malignancy. This review evaluates where genomics is routinely used in clinical care and where opportunities for further application exist. Recent Findings The 2016 revision of the WHO classification of tumours of haematopoietic and lymphoid tissues increased the number of disease entities defined by, or whose diagnosis was strongly supported by, a specific genetic change. Increasingly combinations of mutations rather than individual lesions are being used to genomically classify heterogeneous disorders to inform prognosis and direct treatment. Furthermore, the role of different genetic aberrations as markers of measurable residual disease is being evaluated in clinical trials to allow intensification/de-intensification of treatment as appropriate and early detection of relapse. Summary Implementation of broader sequencing technologies such as whole exome/genome sequencing coupled with continuing developments in genomic technology to improve turn-around-times are likely to further reinforce the centrality of genomics in the management of haematological malignancies.

scholarly journals Role of a genetic variation in the microRNA-4421 binding site of ERP29 regarding risk of oropharynx cancer and prognosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juliana Carron ◽  
Ana Paula Dalla Costa ◽  
José Augusto Rinck-Junior ◽  
Fernanda Viviane Mariano ◽  
Benilton de Sá Carvalho ◽  
...  
Keyword(s):  
Binding Site ◽  
Luciferase Reporter ◽  
Data Validation ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Kaplan Meier ◽  
Genome Wide ◽  
Variant Genotype ◽  
Stage 1

Abstract We conducted a two-stage association study on patients with oropharynx (OP) squamous cell carcinoma (SCC) and healthy controls to identify single nucleotide variants (SNVs) located at the microRNA (miR)-binding sites of carcinogenesis genes associated with risk and prognosis of the disease. In stage 1, 49 patients and 49 controls were analyzed using Genome-Wide Human SNV Arrays to identify variants in the 3′-untranslated region (3′-UTR) of carcinogenesis-related genes, and one SNV was selected for data validation in stage 2 by TaqMan assays in 250 OPSCC patients and 250 controls. The ERP29 c.*293A > G (rs7114) SNV located at miR-4421 binding site was selected for data validation among 46 SNVs. The ERp29 and miR-4421 levels were evaluated by quantitative-PCR and Western blotting. Interaction between miR-4421 with 3′-UTR of ERP29 was evaluated by luciferase reporter assay. Event-free survival (EFS) was calculated by Kaplan–Meier and Cox methods. ERP29 GG variant genotype was more common in OPSCC patients than in controls (6.4% vs 3.6%, p = 0.02; odds ratio: 5.67; 95% confidence interval (CI) 1.27–25.26). Shorter EFS were seen in the base of tongue (BT) SCC patients with GG genotype (0.0% vs 36.2%, p = 0.01; hazard ratio: 2.31; 95% CI: 1.03–5.15). Individuals with ERP29 AG or GG genotypes featured lower levels of ERP29 mRNA (p = 0.005), ERp29 protein (p < 0.001) and higher levels of miR-4421 (p = 0.02). The miR-4421 showed more efficient binding with 3′-UTR of the variant G allele when compared with wild-type allele A (p = 0.001). Our data suggest that ERP29 rs7114 SNV may alter the risk and prognosis of OPSCC due to variation in the ERp29 production possibly modulated by miR-4421.

scholarly journals Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics

Science ◽  
2013 ◽  
Vol 342 (6154) ◽  
pp. 1235587 ◽  
Author(s):  
Ekta Khurana ◽  
Yao Fu ◽  
Vincenza Colonna ◽  
Xinmeng Jasmine Mu ◽  
Hyun Min Kang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Similar Pattern ◽  
Cancer Genomics ◽  
Network Centrality ◽  
Computational Tool ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Noncoding Regions ◽  
Cancer Genomes ◽  
Personal Genomes

Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations (“ultrasensitive”) and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, “motif-breakers”). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

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