Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

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Abstract

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort ( n = 64) in comparison with a non-cancer cohort ( n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function ( GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis ( YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

Abstract

Circulating DNA detected in plasma can be used for diagnostic purposes. Here, the authors show that the 5-hydroxymethyl cytosine biomarker from plasma-derived cell free DNA can be used to detect early stage pancreatic cancer.

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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

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The Sequence Alignment/Map format and SAMtools

Heng Li, Bob Handsaker, Alec Wysoker … (2009)

Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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Author and article information

Contributors

Samuel Levy:

ORCID: http://orcid.org/0000-0002-4444-5103

slevy@bluestargenomics.com

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 19 October 2020

Publication date PMC-release: 19 October 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 5270

Affiliations

[1 ]Bluestar Genomics, 185 Berry Street, Lobby 4, Suite 210, San Francisco, CA 94107 USA

[2 ]Bluestar Genomics, 10578 Science Center Drive Suite 210, San Diego, CA 92121 USA

[3 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, UCSF Helen Diller Family Comprehensive Cancer Center, ; San Francisco, CA 94158 USA

[4 ]GRID grid.168010.e, ISNI 0000000419368956, Departments of Bioengineering and Applied Physics, , Stanford University, ; Stanford, CA 94304 USA

[5 ]Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

Author information

Stephen R. Quake http://orcid.org/0000-0002-1613-0809

Samuel Levy http://orcid.org/0000-0002-4444-5103

Article

Publisher ID: 18965

DOI: 10.1038/s41467-020-18965-w

PMC ID: 7572413

PubMed ID: 33077732

SO-VID: 4a031d45-c49b-4d59-889b-8df6280ac7a7

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 December 2018

Date accepted : 18 September 2020

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Keywords: cancer,epigenomics

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ScienceOpen disciplines: Uncategorized

Keywords: cancer, epigenomics

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Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

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Cancer Metabolism

Most cited references 57

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

The Sequence Alignment/Map format and SAMtools

Cancer statistics, 2020

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Cited by 55

Most referenced authors 2,809