scholarly journals Aperture: Accurate detection of structural variations and viral integrations in circulating tumor DNA using an alignment-free algorithm

2020 ◽  
Author(s):  
Hongchao Liu ◽  
Huihui Yin ◽  
Guangyu Li ◽  
Junling Li ◽  
Xiaoyue Wang
Keyword(s):  
Fragment Size ◽  
Repetitive Sequences ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Structural Variations ◽  
Real Patient ◽  
Alignment Free ◽  
Tumor Dna

AbstractBackgroundThe identification of structural variations (SV) and viral integrations in circulating tumor DNA (ctDNA) is a key step in precision oncology that may assist clinicians for treatment selection and monitoring. However, it is challenging to accurately detect low frequency SVs or SVs involving complex junctions in ctDNA sequencing data due to the short fragment size of ctDNA.ResultsHere, we describe Aperture, a new fast SV caller that applies a unique strategy of k-mer based searching, breakpoint detection using binary labels and candidates clustering to detect SVs and viral integrations in high sensitivity, especially when junctions span repetitive regions, followed by a barcode-based filter to ensure specificity. We evaluated the performance of Aperture in stimulated, reference and real datasets. Aperture demonstrates superior sensitivity and specificity in all tests, especially for low dilution test, compared with existing methods. In addition, Aperture is able to predict sites of viral integration and identify complex SVs involving novel insertions and repetitive sequences in real patient data.ConclusionsUsing a novel alignment-free algorithm, Aperture achieves sensitive, specific and fast detection of structural variations and viral integrations, which may enhance the diagnostic value of ctDNA in clinical application. The executable file and source code are freely available at https://github.com/liuhc8/Aperture.

scholarly journals ctDNAtools: An R package to work with sequencing data of circulating tumor DNA

2020 ◽  
Author(s):  
Amjad Alkodsi ◽  
Leo Meriranta ◽  
Annika Pasanen ◽  
Sirpa Leppä
Keyword(s):  
Residual Disease ◽  
Fragment Size ◽  
R Package ◽  
Monte Carlo Sampling ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Sequencing Data ◽  
Liquid Biopsies ◽  
Tumor Dna

AbstractSummarySequencing of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) in minimally-invasive liquid biopsies is rapidly maturing towards clinical utility for cancer diagnostics. However, the publicly available bioinformatics tools for the specialized analysis of ctDNA sequencing data are still scarce. Here, we present the ctDNAtools R package, which provides functionalities for testing minimal residual disease (MRD) and analyzing cfDNA fragmentation. MRD detection in ctDNAtools utilizes a Monte Carlo sampling approach to test ctDNA positivity through tracking a set of pre-detected reporter mutations in follow-up samples. Additionally, ctDNAtools includes various functionalities to study cfDNA fragment size histograms, profiles and fragment ends patterns.AvailabilityThe ctDNAtools package is freely available under MIT license at https://github.com/alkodsi/ctDNAtools.

scholarly journals BIOM-62 SENSITIVE DETECTION AND DISCRIMINATION OF INTRACRANIAL TUMORS BY BLOOD

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii15-ii15
Author(s):  
Farshad Nassiri ◽  
Ankur Chakravarthy ◽  
Shengrui Feng ◽  
Roxana Shen ◽  
Romina Nejad ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Model Performance ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Low Grade ◽  
Learning Approaches ◽  
Intracranial Tumors ◽  
Cell Of Origin ◽  
Tumor Dna

Abstract BACKGROUND The diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Non-invasive diagnostic approaches, particularly for patients with brain tumours, provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. We reasoned that DNA methylation profiles of circulating tumor DNA in blood can be used as a clinically useful biomarker for patients with brain tumors, given the specificity of DNA methylation profiles for cell-of-origin. METHODS We generated methylation profiles on the plasma of 608 patients with cancer (219 intracranial, 388 extracranial) and 60 healthy controls using a cell-free methylated DNA immunoprecipitation combined with deep sequencing (cfMeDIP-seq) approach. Using machine-learning approaches we generated and evaluated models to distinguish brain tumors from extracranial cancers that may metastasize to the brain, as well as additional models to discriminate common brain tumors included in the differential diagnosis of solitary extra-axial and intra-axial tumors. RESULTS We observed high sensitivity and discriminative capacity for our models to distinguish gliomas from other cancerous and healthy patients (AUC=0.99, 95%CI 0.96–1), with similar performance in IDH mutant and wildtype gliomas as well as in lower- and high-grade gliomas. Excluding non-malignant contributors to plasma methylation did not change model performance (AUC=0.982, 95%CI 0.93–1). Models generated to discriminate intracranial tumors from each other also demonstrated high accuracy for common extra-axial tumors (AUCmeningioma=0.89, 95%CI 0.80–0.97; AUChemangiopericytoma=0.95, 95%CI 0.73–1) as well as intra-axial tumors ranging from low-grade indolent glial-neuronal tumors (AUC 0.93, 95%CI 0.80 – 1) to diffuse intra-axial gliomas with distinct molecular composition (AUCIDH-mutant glioma = 0.82, 95%CI 0.66 -0.98; AUCIDH-wildtype-glioma = 0.71, 95%CI 0.53 – 0.9). Plasma cfMeDIP-seq signals originated from corresponding tumor tissue DNA methylation signals (r=0.37, p< 2.2e-16). CONCLUSIONS These results demonstrate the potential for cfMeDIP-seq profiles to not only detect circulating tumor DNA, but to accurately discriminate common intracranial tumors that share cell-of-origin lineages.

scholarly journals Electroanalytical Biosensors for Circulating Tumor DNA Detection—A Brief Review

2021 ◽  
Author(s):  
Zhijia Peng ◽  
Xiaogang Lin ◽  
Weiqi Nian ◽  
Xiaodong Zheng ◽  
Jayne Wu
Keyword(s):  
Real Time ◽  
Point Of Care ◽  
Low Cost ◽  
High Sensitivity ◽  
High Specificity ◽  
Circulating Tumor Dna ◽  
Minimal Invasive ◽  
Diagnosis And Treatment ◽  
Detection Technology ◽  
Tumor Dna

Early diagnosis and treatment have always been highly desired in the fight against cancer, and detection of circulating tumor DNA (ctDNA) has recently been touted as highly promising for early cancer screening. Consequently, the detection of ctDNA in liquid biopsy gains much attention in the field of tumor diagnosis and treatment, which has also attracted research interest from the industry. However, traditional gene detection technology is difficult to achieve low cost, real-time and portable measurement of ctDNA. Electroanalytical biosensors have many unique advantages such as high sensitivity, high specificity, low cost and good portability. Therefore, this review aims to discuss the latest development of biosensors for minimal-invasive, rapid, and real-time ctDNA detection. Various ctDNA sensors are reviewed with respect to their choices of receptor probes, detection strategies and figures of merit. Aiming at the portable, real-time and non-destructive characteristics of biosensors, we analyze their development in the Internet of Things, point-of-care testing, big data and big health.

Identification of putative germline mutations in 10,288 patients undergoing circulating tumor DNA testing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1514-1514 ◽  
Author(s):  
Thomas Paul Slavin ◽  
Kimberly Banks ◽  
Darya Chudova ◽  
Geoffrey R. Oxnard ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Point Mutations ◽  
Read Depth ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Hereditary Cancer Syndrome ◽  
Dna Testing ◽  
Sequencing Data ◽  
Advanced Cancer Patients ◽  
Cancer Syndrome ◽  
Tumor Dna

1514 Background: No studies have yet described incidental detection of germline cancer predisposition mutations using circulating cell-free DNA (cfDNA). Methods: Deidentified cfDNA sequencing data from 10288 advanced cancer patients (pts) undergoing clinical circulating tumor DNA testing (Guardant360, 73 genes) were included in this study. CfDNA was extracted from plasma and quantified. A DNA library was prepared and sequenced to 15,000X average read depth. Using Ingenuity Variant Analysis, point mutations and small indels suspicious for germline origin (allele fraction 40-60%) were classified following American College of Medical Genetics and Genomics guidelines. Results: More than 50 cancer types were studied, including lung (40%), breast (20%), CRC (8%), prostate (6%), and pancreas (3%). Average age was 63.6 years (range:18-95), 42% were male. Of 34,873 putative germline variants identified, 520 (1.5%) were pathogenic or likely pathogenic (PV), 16,939 (49%) were of uncertain significance, and 17,414 (50%) were benign or likely benign. Of the 250 pts (2.4%) with hereditary cancer syndrome gene PVs, 83 were excluded due to high level of somatic tumor burden leaving 167 (1.6%) with putative germline PVs; rates were higher in pts <50 vs >50 overall (3.3% vs 1.4%, p=0.02) and in breast cancer pts (4.3% vs 1.5%, p=0.03). Conclusions: The observed frequency of incidentally identified putative germline PVs is expectedly lower than the true germline rate; however, these findings illustrate that detection from cfDNA is clinically feasible. Importantly, incidental germline findings could impact oncology treatment planning (e.g. PARP inhibitors for BRCA1/2 mutations) and could benefit families via increased surveillance/primary prevention. Further research is needed to explore how to report potential germline results to clinicians using a systems-based approach. [Table: see text]

scholarly journals MA 11.02 Circulating Tumor DNA in Early Stage NSCLC: High Sensitivity Analysis in Low Burden Disease. LUCID Study Update

2017 ◽  
Vol 12 (11) ◽  
pp. S1843-S1844 ◽  
Author(s):  
A. Ruiz-Valdepenas ◽  
K. Heider ◽  
G. Doughton ◽  
W. Qian ◽  
C. Massie ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Early Stage ◽  
High Sensitivity ◽  
Circulating Tumor Dna ◽  
Early Stage Nsclc ◽  
Tumor Dna

scholarly journals Alignment-free filtering for cfNA fusion fragments

2019 ◽  
Vol 35 (14) ◽  
pp. i225-i232 ◽  
Author(s):  
Xiao Yang ◽  
Yasushi Saito ◽  
Arjun Rao ◽  
Hyunsung John Kim ◽  
Pranav Singh ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Cell Line ◽  
De Novo ◽  
High Sensitivity ◽  
Detection Methods ◽  
Rna Seq ◽  
Sequencing Data ◽  
Alignment Free ◽  
Fusion Detection ◽  
High Depth

Abstract Motivation Cell-free nucleic acid (cfNA) sequencing data require improvements to existing fusion detection methods along multiple axes: high depth of sequencing, low allele fractions, short fragment lengths and specialized barcodes, such as unique molecular identifiers. Results AF4 was developed to address these challenges. It uses a novel alignment-free kmer-based method to detect candidate fusion fragments with high sensitivity and orders of magnitude faster than existing tools. Candidate fragments are then filtered using a max-cover criterion that significantly reduces spurious matches while retaining authentic fusion fragments. This efficient first stage reduces the data sufficiently that commonly used criteria can process the remaining information, or sophisticated filtering policies that may not scale to the raw reads can be used. AF4 provides both targeted and de novo fusion detection modes. We demonstrate both modes in benchmark simulated and real RNA-seq data as well as clinical and cell-line cfNA data. Availability and implementation AF4 is open sourced, licensed under Apache License 2.0, and is available at: https://github.com/grailbio/bio/tree/master/fusion.

scholarly journals Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology

2021 ◽  
Author(s):  
Ira W. Deveson ◽  
◽  
Binsheng Gong ◽  
Kevin Lai ◽  
Jennifer S. LoCoco ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Circulating Tumor Dna ◽  
Precision Oncology ◽  
Tumor Dna

scholarly journals Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17516-e17516 ◽  
Author(s):  
Ashleigh Porter ◽  
Gregory A. Daniels ◽  
Sandip Pravin Patel ◽  
Assuntina Gesualda Sacco ◽  
Kimberly Banks ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Salivary Gland ◽  
Targeted Therapy ◽  
Next Generation Sequencing ◽  
Head And Neck ◽  
Circulating Tumor Dna ◽  
Sequencing Data ◽  
Blood Samples ◽  
Tumor Dna ◽  
Generation Sequencing

e17516 Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is an increasingly prevalent disease but effective targeted therapy is lacking. The use of next generation sequencing (NGS) in the identification of novel targets has been suggested as a way to potentially expand therapeutic options and thereby improve outcomes. Methods: Data was collected on patients with recurrent and metastatic (R/M) head and neck cancers who underwent molecular profiling of blood samples utilizing Guardant360, a 70-gene circulating tumor DNA (ctDNA) NGS platform. CtDNA sequencing data was compared to tumor NGS data, when available. Best response to therapy was assessed using RECIST measures. Results: 60 HNSCC patients were evaluated from February 2015 to June 2016. The most common tumor type and histology was oropharyngeal squamous cell carcinoma (n = 21), which was commonly human papillomavirus (HPV) positive (n = 15). Other cancer types included salivary gland and thyroid cancers. The most common mutations identified by ctDNA analysis were TP53 (98%), PIK3CA (43%), NOTCH1 (38%), and ARID1A (36%). These findings were consistent with results from tumor sequencing data (n = 29) where TP53 (48%) and PIK3CA(24%) were also reported with the highest frequency. Importantly, 73% (n = 22) of patients had alterations identified in ctDNA that were not present in tumor specimens. Actionable mutations were identified in 66% of HNSCC and in 50% salivary gland cancer patients. Of patients with actionable mutations, 10% (n = 6) received matched targeted therapy (MTT): 3 (50%) had stable disease (SD), 1 had progressive disease (PD), and 2 were not evaluated. Of those who did not receive targeted therapy (n = 23), 1 (4.3%) patient had a complete response treated with immunotherapy, 11 (47%) had SD, and 11 (47%) had PD. Conclusions: Analysis of ctDNA may play a role in management decisions in R/M HNSCC. The majority of patients had unique mutations identified on ctDNA. The utility of ctDNA NGS and its role in patient management should be explored in future studies.

Sign in / Sign up

Export Citation Format

Share Document