RT Journal Article
SR Electronic
T1 Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.25.525462
DO 10.1101/2023.01.25.525462
A1 Martin S. Taylor
A1 Connie Wu
A1 Peter C. Fridy
A1 Yasmeen Senussi
A1 Wen-Chih Cheng
A1 John Heaps
A1 Kei Mori
A1 Limor Cohen
A1 Kelly R. Molloy
A1 Brian T. Chait
A1 Michael Goggins
A1 Irun Bhan
A1 Joseph W. Franses
A1 Xiaoyu Yang
A1 Mary-Ellen Taplin
A1 Xinan Wang
A1 David C. Christiani
A1 Bruce E. Johnson
A1 Matthew Meyerson
A1 Ravindra Uppaluri
A1 Ann Marie Egloff
A1 Elyssa N. Denault
A1 Laura M. Spring
A1 Tian-Li Wang
A1 Ie-Ming Shih
A1 Euihye Jung
A1 Kshitij S. Arora
A1 Lawrence R. Zukerberg
A1 Osman H. Yilmaz
A1 Gary Chi
A1 Bryanna L. Norden
A1 Yuhui Song
A1 Linda Nieman
A1 Aparna R. Parikh
A1 Matthew Strickland
A1 Tomas Mustelin
A1 George Eng
A1 Ömer H. Yilmaz
A1 Ursula A. Matulonis
A1 Steven J. Skates
A1 Bo R. Rueda
A1 Ronny Drapkin
A1 Samuel J. Klempner
A1 Vikram Deshpande
A1 David T. Ting
A1 Michael P. Rout
A1 John LaCava
A1 David R. Walt
A1 Kathleen H. Burns
YR 2023
UL http://biorxiv.org/content/early/2023/01/25/2023.01.25.525462.abstract
AB Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1, L1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible detectable expression in corresponding normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore the potential of ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 M) ORF1p concentrations in patient plasma samples across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, and provides early therapeutic response monitoring in gastric and esophageal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring.Competing Interest StatementMST has received consulting fees from ROME Therapeutics and Tessera Therapeutics that are not related to this work. MST and JL have equity in ROME therapeutics. DTT has received consulting fees from ROME Therapeutics, Tekla Capital, Ikena Oncology, Foundation Medicine, Inc., NanoString Technologies, and Pfizer that are not related to this work. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. DTT receives research support from ACD-Biotechne, PureTech Health LLC, Ribon Therapeutics, and Incyte, which was not used in this work. LMS declares the following relationships: Consultant/advisory board: Novartis, Puma, G1 therapeutics, Daiichi Pharma, Astra Zeneca; Institutional research support: Phillips, Merck, Genentech, Gilead, Eli Lilly. SJK declares Consulting/advisory: Eli Lilly, Merck, BMS, Novartis, Astellas, AstraZeneca, Daiichi-Sankyo, Novartis, Sanofi-Aventis, Natera, Exact Sciences, Mersana. Stock/Equity: Turning Point Therapeutics, Nuvalent. BRR serves on SAB for VincenTech and receives research support from Novartis Institutes for Biomedical Research that are not related to this work. DRW has a financial interest in Quanterix Corporation, a company that develops an ultra-sensitive digital immunoassay platform. He is an inventor of the Simoa technology, a founder of the company and also serves on its Board of Directors. KHB declares relationships with Alamar Biosciences, Genscript, Oncolinea/PrimeFour Therapeutics, ROME Therapeutics, Scaffold Therapeutics, Tessera Therapeutics, and Transposon Therapeutics. MST and KHB receive royalties from sales of ORF1p antibodies and MST, CW, PCF, KRM, BTC, MPR, JL, DRW, and KHB are inventors on a patent related to this work.