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

被引：119

作者：

Guler, Gulfem D. ^{[1
]}

Ning, Yuhong ^{[1
]}

Ku, Chin-Jen ^{[1
]}

Phillips, Tierney ^{[2
]}

McCarthy, Erin ^{[2
]}

Ellison, Christopher K. ^{[2
]}

Bergamaschi, Anna ^{[2
]}

Collin, Francois ^{[1
]}

Lloyd, Paul ^{[1
]}

Scott, Aaron ^{[1
]}

Antoine, Michael ^{[2
]}

Wang, Wendy ^{[2
]}

Chau, Kim ^{[1
]}

Ashworth, Alan ^{[3
]}

Quake, Stephen R. ^{[4
,5
,6
]}

Levy, Samuel ^{[1
,2
]}

机构：

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

[2] Bluestar Genom, 10578 Sci Ctr Dr Suite 210, San Diego, CA 92121 USA

[3] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[4] Stanford Univ, Dept Bioengn, Stanford, CA 94304 USA

[5] Stanford Univ, Dept Appl Phys, Stanford, CA 94304 USA

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

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

ADENOCARCINOMA; SUBTYPES; TUMOR; BIOMARKERS; MANAGEMENT; DIAGNOSIS; COMPLEX; LIVER;

D O I：

10.1038/s41467-020-18965-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. 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.

引用

页数：12

共 59 条

[1] Alcohol and Tobacco Lower the Age of Presentation in Sporadic Pancreatic Cancer in a Dose-Dependent Manner: A Multicenter Study [J].

Anderson, Michelle A. ;

Zolotarevsky, Eugene ;

Cooper, Kristine L. ;

Sherman, Simon ;

Shats, Oleg ;

Whitcomb, David C. ;

Lynch, Henry T. ;

Ghiorzo, Paola ;

Rubinstein, Wendy S. ;

Vogel, Kristen J. ;

Sasson, Aaron R. ;

Grizzle, William E. ;

Ketcham, Marsha A. ;

Lee, Shih-Yuan ;

Normolle, Daniel ;

Plonka, Caitlyn M. ;

Mertens, Amy N. ;

Tripon, Renee C. ;

Brand, Randall E. .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2012, 107 (11) :1730-1739

[2] Genomic analyses identify molecular subtypes of pancreatic cancer [J].

Bailey, Peter ;

Chang, David K. ;

Nones, Katia ;

Johns, Amber L. ;

Patch, Ann-Marie ;

Gingras, Marie-Claude ;

Miller, David K. ;

Christ, Angelika N. ;

Bruxner, Tim J. C. ;

Quinn, Michael C. ;

Nourse, Craig ;

Murtaugh, L. Charles ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Manning, Suzanne ;

Nourbakhsh, Ehsan ;

Wani, Shivangi ;

Fink, Lynn ;

Holmes, Oliver ;

Chin, Vencssa ;

Anderson, Matthew J. ;

Kazakoff, Stephen ;

Leonard, Conrad ;

Newell, Felicity ;

Waddell, Nick ;

Wood, Scott ;

Xu, Qinying ;

Wilson, Peter J. ;

Cloonan, Nicole ;

Kassahn, Karin S. ;

Taylor, Darrin ;

Quek, Kelly ;

Robertson, Alan ;

Pantano, Lorena ;

Mincarelli, Laura ;

Sanchez, Luis N. ;

Evers, Lisa ;

Wu, Jianmin ;

Pinese, Mark ;

Cowley, Mark J. ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chantrill, Lorraine A. ;

Mawson, Amanda ;

Humphris, Jeremy ;

Chou, Angela ;

Pajic, Marina ;

Scarlett, Christopher J. .

NATURE, 2016, 531 (7592) :47-+

[3] The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal [J].

Ballehaninna, Umashankar K. ;

Chamberlain, Ronald S. .

JOURNAL OF GASTROINTESTINAL ONCOLOGY, 2012, 3 (02) :105-119

[4] Inflammation-Induced NFATc1-STAT3 Transcription Complex Promotes Pancreatic Cancer Initiation by KrasG12D [J].

Baumgart, Sandra ;

Chen, Nai-Ming ;

Siveke, Jens T. ;

Koenig, Alexander ;

Zhang, Jin-San ;

Singh, Shiv K. ;

Wolf, Elmar ;

Bartkuhn, Marek ;

Esposito, Irene ;

Hessmann, Elisabeth ;

Reinecke, Johanna ;

Nikorowitsch, Julius ;

Brunner, Marius ;

Singh, Garima ;

Fernandez-Zapico, Martin E. ;

Smyrk, Thomas ;

Bamlet, William R. ;

Eilers, Martin ;

Neesse, Albrecht ;

Gress, Thomas M. ;

Billadeau, Daniel D. ;

Tuveson, David ;

Urrutia, Raul ;

Ellenrieder, Volker .

CANCER DISCOVERY, 2014, 4 (06) :688-701

[5] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[6] Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes [J].

Biankin, Andrew V. ;

Waddell, Nicola ;

Kassahn, Karin S. ;

Gingras, Marie-Claude ;

Muthuswamy, Lakshmi B. ;

Johns, Amber L. ;

Miller, David K. ;

Wilson, Peter J. ;

Patch, Ann-Marie ;

Wu, Jianmin ;

Chang, David K. ;

Cowley, Mark J. ;

Gardiner, Brooke B. ;

Song, Sarah ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Nourse, Craig ;

Nourbakhsh, Ehsan ;

Manning, Suzanne ;

Wani, Shivangi ;

Gongora, Milena ;

Pajic, Marina ;

Scarlett, Christopher J. ;

Gill, Anthony J. ;

Pinho, Andreia V. ;

Rooman, Ilse ;

Anderson, Matthew ;

Holmes, Oliver ;

Leonard, Conrad ;

Taylor, Darrin ;

Wood, Scott ;

Xu, Qinying ;

Nones, Katia ;

Fink, J. Lynn ;

Christ, Angelika ;

Bruxner, Tim ;

Cloonan, Nicole ;

Kolle, Gabriel ;

Newell, Felicity ;

Pinese, Mark ;

Mead, R. Scott ;

Humphris, Jeremy L. ;

Kaplan, Warren ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chou, Angela ;

Chin, Venessa T. ;

Chantrill, Lorraine A. .

NATURE, 2012, 491 (7424) :399-405

[7] BAGE - A NEW GENE ENCODING AN ANTIGEN RECOGNIZED ON HUMAN MELANOMAS BY CYTOLYTIC T-LYMPHOCYTES [J].

BOEL, P ;

WILDMANN, C ;

SENSI, ML ;

BRASSEUR, R ;

RENAULD, JC ;

COULIE, P ;

BOON, T ;

VANDERBRUGGEN, P .

IMMUNITY, 1995, 2 (02) :167-175

[8] Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm [J].

Burke, Z ;

Oliver, G .

MECHANISMS OF DEVELOPMENT, 2002, 118 (1-2) :147-155

[9] Modification of Enhancer Chromatin: What, How, and Why? [J].

Calo, Eliezer ;

Wysocka, Joanna .

MOLECULAR CELL, 2013, 49 (05) :825-837

[10] Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma [J].

Aguirre, Andrew J. ;

Hruban, Ralph H. ;

Raphael, Benjamin J. .

CANCER CELL, 2017, 32 (02) :185-+

← 1 2 3 4 5 6 →