Enhanced detection of circulating tumor DNA by fragment size analysis

Florent Mouliere; Dineika Chandrananda; Anna M. Piskorz; Elizabeth K. Moore; James Morris; Lise Barlebo Ahlborn; Richard Mair; Teodora Goranova; Francesco Marass; Katrin Heider; Jonathan C. M. Wan; Anna Supernat; Irena Hudecova; Ioannis Gounaris; Susana Ros; Mercedes Jimenez-Linan; Javier Garcia-Corbacho; Keval Patel; Olga Østrup; Suzanne Murphy; Matthew D. Eldridge; Davina Gale; Grant D. Stewart; Johanna Burge; Wendy N. Cooper; Michiel S. van der Heijden; Charles E. Massie; Colin Watts; Pippa Corrie; Simon Pacey; Kevin M. Brindle; Richard D. Baird; Morten Mau-Sørensen; Christine A. Parkinson; Christopher G. Smith; James D. Brenton; Nitzan Rosenfeld

doi:10.1126/scitranslmed.aat4921

Research ArticleCancer

Enhanced detection of circulating tumor DNA by fragment size analysis

View ORCID ProfileFlorent Mouliere¹,²,*,†,
View ORCID ProfileDineika Chandrananda¹,²,*,
View ORCID ProfileAnna M. Piskorz¹,²,*,
View ORCID ProfileElizabeth K. Moore¹,²,³,*,
James Morris¹,²,
Lise Barlebo Ahlborn⁴,⁵,
Richard Mair¹,²,⁶,
View ORCID ProfileTeodora Goranova¹,²,
View ORCID ProfileFrancesco Marass¹,²,⁷,⁸,
View ORCID ProfileKatrin Heider¹,²,
View ORCID ProfileJonathan C. M. Wan¹,²,
Anna Supernat¹,²,⁹,
View ORCID ProfileIrena Hudecova¹,²,
Ioannis Gounaris¹,²,³,
Susana Ros¹,²,
Mercedes Jimenez-Linan²,³,
Javier Garcia-Corbacho¹⁰,
Keval Patel¹,²,
Olga Østrup⁵,
Suzanne Murphy¹,²,
View ORCID ProfileMatthew D. Eldridge¹,²,
View ORCID ProfileDavina Gale¹,²,
View ORCID ProfileGrant D. Stewart²,³,¹¹,
Johanna Burge²,¹¹,
View ORCID ProfileWendy N. Cooper¹,²,
Michiel S. van der Heijden¹²,¹³,
View ORCID ProfileCharles E. Massie¹,²,¹⁴,
View ORCID ProfileColin Watts¹⁵,
View ORCID ProfilePippa Corrie³,
Simon Pacey³,¹⁴,
View ORCID ProfileKevin M. Brindle¹,²,¹⁶,
View ORCID ProfileRichard D. Baird¹⁷,
View ORCID ProfileMorten Mau-Sørensen⁴,
Christine A. Parkinson¹,²,³,¹⁸,¹⁹,
View ORCID ProfileChristopher G. Smith¹,²,
View ORCID ProfileJames D. Brenton¹,²,³,¹⁸,¹⁹,‡,§ and
View ORCID ProfileNitzan Rosenfeld ¹,²,‡,§

¹Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.
²Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.
³Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.
⁴Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
⁵Centre for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
⁶Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, CB2 0QQ Cambridge, UK.
⁷Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
⁸Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.
⁹Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-211 Gdańsk, Poland.
¹⁰Clinical Trials Unit, Clinic Institute of Haematological and Oncological Diseases, Hospital Clinic de Barcelona, 170 08036 Barcelona, Spain.
¹¹Academic Urology Group, Department of Surgery, University of Cambridge, CB2 0QQ Cambridge, UK.
¹²Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
¹³Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
¹⁴Department of Oncology, University of Cambridge, CB2 0XZ Cambridge, UK.
¹⁵Institute of Cancer Genomics Science, University of Birmingham, B15 2TT Birmingham, UK.
¹⁶Department of Biochemistry, University of Cambridge, CB2 1QW Cambridge, UK.
¹⁷Early Phase Clinical Trials and Breast Cancer Research Teams, Cancer Research UK Cambridge Centre, CB2 0QQ Cambridge, UK.
¹⁸Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, CB2 0XZ Cambridge, UK.
¹⁹NIHR Cambridge Biomedical Research Centre, CB2 0QQ Cambridge, UK.

↵§Corresponding author. Email: james.brenton{at}cruk.cam.ac.uk (J.D.B.); nitzan.rosenfeld{at}cruk.cam.ac.uk (N.R.)

↵* These authors contributed equally to this work as co-first authors.
↵† Present address: Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, de Boelelaan 1117, 1081 HV Amsterdam, Netherlands.
↵‡ These authors contributed equally to this work as co-senior authors.

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Science Translational Medicine 07 Nov 2018:
Vol. 10, Issue 466, eaat4921
DOI: 10.1126/scitranslmed.aat4921

Florent Mouliere

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Dineika Chandrananda

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Anna M. Piskorz

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Elizabeth K. Moore

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

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James Morris

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Lise Barlebo Ahlborn

4Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

5Centre for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

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Richard Mair

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

6Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, CB2 0QQ Cambridge, UK.

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Teodora Goranova

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Francesco Marass

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

7Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.

8Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.

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Katrin Heider

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Jonathan C. M. Wan

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Anna Supernat

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

9Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-211 Gdańsk, Poland.

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Irena Hudecova

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Ioannis Gounaris

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

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Susana Ros

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Mercedes Jimenez-Linan

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

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Javier Garcia-Corbacho

10Clinical Trials Unit, Clinic Institute of Haematological and Oncological Diseases, Hospital Clinic de Barcelona, 170 08036 Barcelona, Spain.

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Keval Patel

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Olga Østrup

5Centre for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

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Suzanne Murphy

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Matthew D. Eldridge

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Davina Gale

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Grant D. Stewart

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

11Academic Urology Group, Department of Surgery, University of Cambridge, CB2 0QQ Cambridge, UK.

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Johanna Burge

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

11Academic Urology Group, Department of Surgery, University of Cambridge, CB2 0QQ Cambridge, UK.

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Wendy N. Cooper

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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Michiel S. van der Heijden

12Division of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.

13Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.

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Charles E. Massie

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

14Department of Oncology, University of Cambridge, CB2 0XZ Cambridge, UK.

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Colin Watts

15Institute of Cancer Genomics Science, University of Birmingham, B15 2TT Birmingham, UK.

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Pippa Corrie

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

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Simon Pacey

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

14Department of Oncology, University of Cambridge, CB2 0XZ Cambridge, UK.

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Kevin M. Brindle

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

16Department of Biochemistry, University of Cambridge, CB2 1QW Cambridge, UK.

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Richard D. Baird

17Early Phase Clinical Trials and Breast Cancer Research Teams, Cancer Research UK Cambridge Centre, CB2 0QQ Cambridge, UK.

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Morten Mau-Sørensen

4Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

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Christine A. Parkinson

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

18Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, CB2 0XZ Cambridge, UK.

19NIHR Cambridge Biomedical Research Centre, CB2 0QQ Cambridge, UK.

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Christopher G. Smith

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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James D. Brenton

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

3Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

18Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, CB2 0XZ Cambridge, UK.

19NIHR Cambridge Biomedical Research Centre, CB2 0QQ Cambridge, UK.

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For correspondence: james.brenton@cruk.cam.ac.uk nitzan.rosenfeld@cruk.cam.ac.uk

Nitzan Rosenfeld

1Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE Cambridge, UK.

2Cancer Research UK Major Centre–Cambridge, Cancer Research UK Cambridge Institute, CB2 0RE Cambridge, UK.

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For correspondence: james.brenton@cruk.cam.ac.uk nitzan.rosenfeld@cruk.cam.ac.uk

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Sizing up circulating tumor DNA

Unlike solid tumors, which are often hidden deep within a patient’s body, a patient’s blood is easy to access safely. As a result, liquid biopsy, the analysis of tumor DNA in the blood, is an attractive alternative to conventional biopsy. Unfortunately, tumor DNA molecules are usually vastly outnumbered by the fragments of noncancer DNA in the blood, and detecting them can be a challenge, especially in early stages of cancer. Mouliere et al. identified characteristic differences in the size distribution of tumor-derived and noncancer DNA fragments and then used these observations to design a method of tumor DNA detection with greater sensitivity.

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Enhanced detection of circulating tumor DNA by fragment size analysis

Sizing up circulating tumor DNA

Science Translational Medicine

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