Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

Published on Jun 1, 2020in Nature Medicine36.13
· DOI :10.1038/S41591-020-0915-3
Asaf Zviran9
Estimated H-index: 9
(Cornell University),
Rafael C. Schulman5
Estimated H-index: 5
(Cornell University)
+ 39 AuthorsDan A. Landau24
Estimated H-index: 24
(Cornell University)
Sources
Abstract
In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10−5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care. A new approach for whole-genome sequencing of plasma circulating tumor DNA allows for dynamic monitoring of disease burden and ultra-sensitive detection of minimal residual disease.
📖 Papers frequently viewed together
3 Citations
592 Citations
References48
Newest
#1Ronen Sadeh (HUJI: Hebrew University of Jerusalem)H-Index: 6
#2Israa Sharkia (HUJI: Hebrew University of Jerusalem)H-Index: 3
Last. Nir Friedman (HUJI: Hebrew University of Jerusalem)H-Index: 101
view all 31 authors...
Blood cell-free DNA (cfDNA) is derived from fragmented chromatin in dying cells. As such, it remains associated with histones that may retain the covalent modifications present in the cell of origin. Until now this rich epigenetic information carried by cell-free nucleosomes has not been explored at the genome level. Here, we perform ChIP-seq of cell free nucleosomes (cfChIP-seq) directly from human blood plasma to sequence DNA fragments from nucleosomes carrying specific chromatin marks. We ass...
8 CitationsSource
#1Pedram Razavi (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 28
#2Bob T. Li (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 33
Last. Jorge S. Reis-Filho (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 133
view all 43 authors...
Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tiss...
189 CitationsSource
#1Thomas Reinert (Aarhus University Hospital)H-Index: 17
#2Tenna V Henriksen (Aarhus University Hospital)H-Index: 2
Last. Claus L. Andersen (Aarhus University Hospital)H-Index: 55
view all 38 authors...
Importance Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC). Objective To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients w...
161 CitationsSource
#1Yuxuan Wang (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 26
#2Lu Li (Johns Hopkins University)H-Index: 13
Last. Louise Olsson (Karolinska University Hospital)H-Index: 5
view all 16 authors...
Importance For patients with resected, nonmetastatic colorectal cancer (CRC), the optimal surveillance protocol remains unclear. Objective To evaluate whether serial circulating tumor DNA (ctDNA) levels detected disease recurrence earlier, compared with conventional postoperative surveillance, in patients with resected CRC. Design, Setting, and Participants This study included patients (n = 58) with stage I, II, or III CRC who underwent radical surgical resection at 4 Swedish hospitals from Febr...
58 CitationsSource
#1Jesse J. Salk (UW: University of Washington)H-Index: 17
#2Kaitlyn Loubet-Senear (UW: University of Washington)H-Index: 3
Last. Rosa Ana Risques (UW: University of Washington)H-Index: 25
view all 18 authors...
Summary High-accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer detection using ultra-accurate Duplex Sequencing to identify TP53 mutations in uterine lavage. However, in addition to tumor DNA, we also detect low-frequency TP53 mutations in nearly all lavages from women with and without cancer. These mutatio...
38 CitationsSource
#1Stephen Cristiano (Johns Hopkins University)H-Index: 5
#2Alessandro Leal (Johns Hopkins University)H-Index: 7
Last. Victor E. Velculescu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 106
view all 36 authors...
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 ...
241 CitationsSource
#1Keren Yizhak (Broad Institute)H-Index: 22
#2François Aguet (Broad Institute)H-Index: 36
Last. Gad GetzH-Index: 179
view all 20 authors...
INTRODUCTION Cancer genome studies have contributed to the analysis and discovery of somatic mutations that drive cancer growth. However, studying the genetic makeup of a tumor when it is already fully developed limits our ability to uncover how and which somatic mutations accumulate in normal tissues in the stages preceding cancer initiation. To address this challenge, recent studies performed deep sequencing in a limited number of tissue types and a small number of individuals, identifying a l...
186 CitationsSource
#1Nozomi KarakuchiH-Index: 2
#2Manabu ShimomuraH-Index: 12
Last. Tadateru Takahashi (Life Sciences Institute)H-Index: 4
view all 10 authors...
Background Spontaneous regression (SR) of colorectal cancer (CRC) is extremely rare, and only few cases have been reported. Although it is not yet clarified, a plausible mechanism for SR of CRC is an immunological event.
8 CitationsSource
#1Joshua Moss (HUJI: Hebrew University of Jerusalem)H-Index: 10
#2Judith Magenheim (HUJI: Hebrew University of Jerusalem)H-Index: 16
Last. Yuval Dor (HUJI: Hebrew University of Jerusalem)H-Index: 66
view all 23 authors...
Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cell...
195 CitationsSource
#1Inigo MartincorenaH-Index: 48
#2Joanna C. FowlerH-Index: 8
Last. Philip H. JonesH-Index: 31
view all 15 authors...
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones pe...
407 CitationsSource
Cited By35
Newest
#1Joerg BrednoH-Index: 4
#2Jafi A. LipsonH-Index: 17
Last. Arash JamshidiH-Index: 8
view all 0 authors...
Background null Oncology applications of cell-free DNA analysis are often limited by the amount of circulating tumor DNA and the fraction of cell-free DNA derived from tumor cells in a blood sample. This circulating tumor fraction varies widely between individuals and cancer types. Clinical factors that influence tumor fraction have not been completely elucidated. null Methods and findings null Circulating tumor fraction was determined for breast, lung, and colorectal cancer participant samples ...
Source
#1M.K. Thompson (Cambridge University Hospitals NHS Foundation Trust)
#2Davina Gale (University of Cambridge)H-Index: 15
Last. James D. Brenton (Cambridge University Hospitals NHS Foundation Trust)H-Index: 64
view all 3 authors...
This review introduces clinicians to the basic concepts of the biology of circulating tumour DNA (ctDNA), which is required to understand clinical use of ctDNA technology. We provide an overview of how new technology has improved the sensitivity of ctDNA detection over the last decade and the available techniques for ctDNA analysis including whole-genome sequencing (WGS), targeted cancer-associated gene panels, and methylation analysis. We discuss the most recent evidence from clinical trials fo...
Source
#1Solomon L. Woldu (UTSW: University of Texas Southwestern Medical Center)H-Index: 13
#2Yair Lotan (UTSW: University of Texas Southwestern Medical Center)H-Index: 107
Source
#1Gene Koh (University of Cambridge)H-Index: 3
#2Andrea Degasperi (University of Cambridge)H-Index: 15
Last. Serena Nik-Zainal (University of Cambridge)H-Index: 52
view all 5 authors...
Whole-genome sequencing has brought the cancer genomics community into new territory. Thanks to the sheer power provided by the thousands of mutations present in each patient's cancer, we have been able to discern generic patterns of mutations, termed 'mutational signatures', that arise during tumorigenesis. These mutational signatures provide new insights into the causes of individual cancers, revealing both endogenous and exogenous factors that have influenced cancer development. This Review b...
Source
#1Dimitrios Mathios (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 15
#2Siddhartha Srivastava (JHUSOM: Johns Hopkins University School of Medicine)
Last. Michael Lim (Stanford University)H-Index: 53
view all 5 authors...
Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, ad...
Source
#1Alexandre Pellan Cheng (Cornell University)H-Index: 6
#2Matthew P Cheng (Brigham and Women's Hospital)H-Index: 19
Last. Emily Silverman (Brigham and Women's Hospital)H-Index: 3
view all 14 authors...
Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of post-transplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a highly versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT; infection; relapse of underlying disease;...
2 CitationsSource
#1Estelle BourbonH-Index: 1
#2Vincent AlcazerH-Index: 6
Last. Pierre Sujobert (University of Lyon)H-Index: 17
view all 5 authors...
The analysis of circulating tumor DNA (ctDNA) released by tumor cells holds great promise for patients with lymphoma, to refine the diagnostic procedure, clarify the prognosis, monitor the response to treatment, and detect relapses earlier. One of the main challenges of the coming years is to adapt techniques from highly specialized translational teams to routine laboratories as this requires a careful technical and clinical validation, and we have to achieve this as fast as possible to transfor...
Source
The start-up C2i Genomics is hoping to improve liquid biopsies with its platform for detecting rare tumour DNA in blood samples. null The start-up C2i Genomics is hoping to improve liquid biopsies with its platform for detecting rare tumour DNA in blood samples.
Source
#1Justin M. Burgener (Princess Margaret Cancer Centre)H-Index: 2
#2Jinfeng Zou (Princess Margaret Cancer Centre)H-Index: 14
Last. Geoffrey Liu (Princess Margaret Cancer Centre)H-Index: 78
view all 19 authors...
Purpose: null Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naive methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naive detection of ctDNA by simultaneous profiling of mutations and methylation. null Experimental Design: null We con...
Source
Abstract null null Background null Breast malignancy is the most frequently diagnosed malignancy in women worldwide, and the diagnosis relies on invasive examinations. However, most clinical breast changes in women are benign, and invasive diagnostic approaches cause unnecessary suffering for the patients. Thus, a novel noninvasive approach for discriminating malignant breast lesions from benign lesions is needed. null null null Methods null We performed cell-free DNA (cfDNA) sequencing on plasm...
Source