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PMID: 24705333 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.

Nature medicine ·Vol. 20 ·No. 5 ·2014-05-00 ·Pages 548-54

Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, Liu CL, Neal JW, Wakelee HA, Merritt RE, Shrager JB, Loo BW, Alizadeh AA, Diehn M

Abstract

Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

MeSH Terms
Biomarkers, Tumor/blood Carcinoma, Non-Small-Cell Lung/blood,diagnosis,genetics DNA, Neoplasm/blood,isolation & purification High-Throughput Nucleotide Sequencing Humans Neoplasm Staging Neoplasms/blood,diagnosis,genetics Neoplastic Cells, Circulating/metabolism
Chemicals
Biomarkers, Tumor DNA, Neoplasm
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Newman Aaron M
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA. [3].
Bratman Scott V
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Department of Radiation Oncology, Stanford University, Stanford, California, USA. [3].
To Jacqueline
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
Wynne Jacob F
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
Eclov Neville C W
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
Modlin Leslie A
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
Liu Chih Long
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
Neal Joel W
Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
Wakelee Heather A
Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
Merritt Robert E
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Shrager Joseph B
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Loo Billy W ORCID
Department of Radiation Oncology, Stanford University, Stanford, California, USA.
Alizadeh Ash A
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA. [3] Division of Hematology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
Diehn Maximilian ORCID
1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [2] Department of Radiation Oncology, Stanford University, Stanford, California, USA. [3] Stanford Cancer Institute, Stanford University, Stanford, California, USA.
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.3519
Published
2014-05-00
Epub
2014-00-06
Pages
548-54
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC4016134
Subset
IM
Grants
NCI NIH HHS · DP2 CA186569 · United States
NCI NIH HHS · T32 CA009302 · United States
NCI NIH HHS · 1-DP2-CA186569 · United States
Databases
SRA
SRP040228
Corrections
CommentIn
PMID: 24804754
External Links
PubMed source DOI: 10.1038/nm.3519 PMC Full Text View journal details
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