Detection of aneuploidy in patients with cancer through amplification of long interspersed nucleotide elements (LINEs)

Christopher Douville; Simeon Springer; Isaac Kinde; Joshua D Cohen; Ralph H Hruban; Anne Marie Lennon; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Rachel Karchin

doi:10.1073/pnas.1717846115

Detection of aneuploidy in patients with cancer through amplification of long interspersed nucleotide elements (LINEs)

Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):1871-1876. doi: 10.1073/pnas.1717846115. Epub 2018 Feb 5.

Authors

Christopher Douville^{1

2}, Simeon Springer^{3

4

5}, Isaac Kinde⁶, Joshua D Cohen^{1

3

4

5}, Ralph H Hruban^{7

8}, Anne Marie Lennon^{9

10

11}, Nickolas Papadopoulos^{3

5}, Kenneth W Kinzler^{3

5}, Bert Vogelstein^{12

4

5}, Rachel Karchin^{13

2

7}

Affiliations

¹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287.
² Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287.
³ Ludwig Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁴ Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁵ Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁶ PapGene, Inc., Baltimore, MD 21211.
⁷ Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁸ Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
⁹ The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹⁰ Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹¹ Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
¹² Ludwig Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com karchin@jhu.edu.
¹³ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287; bertvog@gmail.com karchin@jhu.edu.

Abstract

Aneuploidy is a feature of most cancer cells, and a myriad of approaches have been developed to detect it in clinical samples. We previously described primers that could be used to amplify ∼38,000 unique long interspersed nucleotide elements (LINEs) from throughout the genome. Here we have developed an approach to evaluate the sequencing data obtained from these amplicons. This approach, called Within-Sample AneupLoidy DetectiOn (WALDO), employs supervised machine learning to detect the small changes in multiple chromosome arms that are often present in cancers. We used WALDO to search for chromosome arm gains and losses in 1,677 tumors and in 1,522 liquid biopsies of blood from cancer patients or normal individuals. Aneuploidy was detected in 95% of cancer biopsies and in 22% of liquid biopsies. Using single-nucleotide polymorphisms within the amplified LINEs, WALDO concomitantly assesses allelic imbalances, microsatellite instability, and sample identification. WALDO can be used on samples containing only a few nanograms of DNA and as little as 1% neoplastic content and has a variety of applications in cancer diagnostics and forensic science.

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*
Chromosome Aberrations
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Long Interspersed Nucleotide Elements / genetics*
Neoplasms / genetics*
Nucleic Acid Amplification Techniques / methods

Abstract

Publication types

MeSH terms

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