Assessing aneuploidy with repetitive element sequencing

Christopher Douville; Joshua D Cohen; Janine Ptak; Maria Popoli; Joy Schaefer; Natalie Silliman; Lisa Dobbyn; Robert E Schoen; Jeanne Tie; Peter Gibbs; Michael Goggins; Christopher L Wolfgang; Tian-Li Wang; Ie-Ming Shih; Rachel Karchin; Anne Marie Lennon; Ralph H Hruban; Cristian Tomasetti; Chetan Bettegowda; Kenneth W Kinzler; Nickolas Papadopoulos; Bert Vogelstein

doi:10.1073/pnas.1910041117

Assessing aneuploidy with repetitive element sequencing

Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4858-4863. doi: 10.1073/pnas.1910041117. Epub 2020 Feb 19.

Authors

Christopher Douville^{1

2

3

4}, Joshua D Cohen^{1

2

3

4

5}, Janine Ptak^{1

2

3

4}, Maria Popoli^{1

2

3

4}, Joy Schaefer^{1

2

3

4}, Natalie Silliman^{1

2

3

4}, Lisa Dobbyn^{1

2

3

4}, Robert E Schoen^{6

7}, Jeanne Tie^{8

9

10

11}, Peter Gibbs^{8

9

10}, Michael Goggins^{2

3

12

13

14}, Christopher L Wolfgang¹⁵, Tian-Li Wang^{2

12

13}, Ie-Ming Shih^{12

16}, Rachel Karchin^{5

13

17}, Anne Marie Lennon^{2

3

13

14

15}, Ralph H Hruban^{12

13}, Cristian Tomasetti^{2

18}, Chetan Bettegowda^{1

2

3

19}, Kenneth W Kinzler^{1

2

3}, Nickolas Papadopoulos^{1

2

3}, Bert Vogelstein^{20

2

3

4}

Affiliations

¹ Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
² Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
³ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
⁴ Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218.
⁶ Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260.
⁷ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15260.
⁸ Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁹ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Department of Medical Oncology, Western Health, Melbourne, VIC 3011, Australia.
¹¹ Department of Medical Oncology, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia.
¹² Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
¹⁴ Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹⁵ Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹⁶ Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore MD 21287.
¹⁷ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
¹⁸ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
¹⁹ Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
²⁰ Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287; vogelbe@jhmi.edu.

Abstract

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.

Keywords: aneuploidy; circulating tumor DNA; early cancer detection; liquid biopsy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aneuploidy*
Biomarkers, Tumor
Circulating Tumor DNA
DNA / genetics
Esophagus
Humans
Liquid Biopsy
Mutation
Neoplasms* / diagnosis
Neoplasms* / genetics
Repetitive Sequences, Nucleic Acid* / genetics
Whole Genome Sequencing

Substances

Biomarkers, Tumor
Circulating Tumor DNA
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding