Genome-wide cell-free DNA fragmentation in patients with cancer

Today, I will give a talk about “Genome-wide cell-free DNA fragmentation in patients with cancer” in MCRI postdoc club meeting. The paper was published in Nature recently. See the slice here or download here for more details.

cfDNA fragmentation in human cancers

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.

Cell-Free DNA Project and Adavance

• 09/29/2019: Shanghai Changhai Hospital: Prospective Estimation on Stool-DNA Screening of Colorectal Cancer
• 09/28/2019: ESMO, GRAIL (Dr. Geoffrey R Oxnard) anounce cfDNA methylation for tissue-of-origin prediction in 20+ cancers

Cell-Free DNA General Background

• Wei Chen, Noninvasive chimeric DNA profiling identifies tumor-originated HBV integrants contributing to viral antigen expression in liver cancer
• Pan et al “Brain Tumor Mutations Detected in Cerebral Spinal Fluid”
• Schilling and Rehli “Global, comparative analysis of tissue-specificpromoter CpG methylation”
• Jahr et al “DNA Fragments in the Blood Plasma of CancerPatients: Quantitations and Evidence for Their Origin from Apoptotic and Necrotic Cells”
• Van der Vaart and Pretorius “Circulating DNAIts Origin and Fluctuation”
• Stroun et al “The Origin and Mechanism of Circulating DNA”
• Gravina et al “The dark side of circulating nucleic acids”
• Sun et al “Plasma DNA tissue mapping by genome-wide methylationsequencing for noninvasive prenatal, cancer, and transplantation assessments”
• Wyatt et al “Concordance of CirculatingTumor DNA and MatchedMetastatic Tissue Biopsy in Prostate Cancer”
• Ma et al “Cell-Free DNA Provides a Good Representationof the Tumor Genome Despite Its Biased Fragmentation Patterns”

Cell-Free DNA and Methylation

• Lehman-Werman et al “Identification of tissue-specific celldeath using methylation patterns of circulating DNA”
• Synder et al “Cell-free DNA Comprises an In Vivo NucleosomeFootprint that Informs Its Tissues-Of-Origin”
• Jensen et al “Whole genome bisulfite sequencing ofcell-free DNA and its cellular contributorsuncovers placenta hypomethylated domains”
• Guo et al “Identification of methylation haplotypeblocks aids in deconvolution of heterogeneoustissue samples and tumortissue-of-origin mapping from plasma DNA”
• Kessler et al “CpG methylation differences betweenneurons and glia are highlyconserved from mouse to human”
• Luck et al “A Stochastic Model for the Formation of SpatialMethylation Patterns”
• Doherty and Couldrey “Exploring genome wide bisulfite sequencing for DNA methylation analysis in livestock: a technical assessment”
• Intro methylation review: “DNA methylation: a form ofepigenetic control of gene expression”
• Koch et al “Analysis of DNA methylation in cancer: location revisited”
• Smith and Meissner “DNA methylation: roles in mammalian development”

Non-CpG Methylation

• Xu and Corces “Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites”

Deconvolution algorithms

• Houseman et al “Reference-freedeconvolution of DNA methylationdata and mediation by cellcomposition effects”
• Rahmani et al “Sparse PCA Corrects forCell-Type Heterogeneity in Epigenome-WideAssociation Studies”
• Gond and Szustakowski “DeconRNASeq: a statistical framework fordeconvolution of heterogeneoustissue samples based on mRNA-Seq data”

WGBS Algorithms

• Michael Scherer, Quantitative comparison of within-sample heterogeneity scores for DNA methylation data
• Ziller et al “Coverage recommendations for methylation analysis by whole genome bisulfite sequencing”
• Merkel et al “gemBS - high throughput processing for DNA methylation data from Bisulfite Sequencing”
• Lee et al “An integrative approach for efficientanalysis of whole genome bisulfite sequencing data”
• Kunde-Ramamoorty et al “Comparison and quantitativeverification of mapping algorithmsfor whole-genome bisulfite sequencing”
• Xi and Li “BSMAP: whole genome bisulfitesequence MAPping program”
• Guo et al “BS-Seeker2: a versatile aligning pipeline for bisulfite sequencing data”
• Krueger and Andrews “Bismark: aflexible aligner and methylationcaller for Bisulfite-Seq applications”
• Feng et al “Disease prediction by cell-free DNA methylation”

Methylation pipeline and analysis tools

• MethylMix 2.0: an R package for identifying DNA methylation genes
• RnBeads 2.0: comprehensive analysis of DNA methylation data
• Bismark:A tool to map bisulfite converted sequence reads and determine cytosine methylation states

• MethPipe: a computational pipeline for analyzing bisulfite sequencing data

• see the slice for the presentation. Also you can download here for more details..

• September 24, 2019 07:00 AM Eastern Daylight Time: CAMBRIDGE, Mass. & SAN CARLOS, Calif.–(BUSINESS WIRE)–Foundation Medicine, Inc. and Natera, Inc. (NASDAQ: NTRA) today announced a partnership to develop and commercialize personalized circulating tumor DNA (ctDNA) monitoring assays, for use by biopharmaceutical and clinical customers who order FoundationOne®CDx. The initial focus of the partnership will be to enable ctDNA monitoring in biopharmaceutical trials in 2020 to establish the clinical utility for these novel assays. Following these studies, a monitoring product will be made available to clinical customers.

• All the figures are only used for non-profit education. reminding me if infrigement happens