Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker

• Published in: bioRxiv
• Main Authors: Taylor, Martin S, Connie, Wu, Fridy, Peter C, Zhang, Stephanie J, Senussi, Yasmeen, Wolters, Justina C, Cheng, Wen-Chih, Heaps, John, Miller, Bryant D, Mori, Kei, Cohen, Limor, Jiang, Hua, Molloy, Kelly R, Norden, Bryanna L, Chait, Brian T, Goggins, Michael, Bhan, Irun, Franses, Joseph W, Yang, Xiaoyu, Taplin, Mary-Ellen, Wang, Xinan, Christiani, David C, Johnson, Bruce E, Meyerson, Matthew, Uppaluri, Ravindra, Egloff, Ann Marie, Denault, Elyssa N, Spring, Laura M, Wang, Tian-Li, Shih, Ie-Ming, Jung, Euihye, Arora, Kshitij S, Zukerberg, Lawrence R, Yilmaz, Osman H, Chi, Gary, Matulonis, Ursula A, Song, Yuhui, Nieman, Linda, Parikh, Aparna R, Strickland, Matthew, Corcoran, Ryan B, Mustelin, Tomas, Eng, George, Yilmaz, Ã-Mer H, Skates, Steven J, Rueda, Bo R, Drapkin, Ronny, Klempner, Samuel J, Deshpande, Vikram, Ting, David T, Rout, Michael P, LaCava, John, Walt, David R, Burns, Kathleen H
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 17.03.2023
• Subjects: Biomarkers; Cancer; Carcinogenesis; Carcinoma; Dithiothreitol; Long interspersed nucleotide elements; Medical research; Ovarian cancer
• DOI: 10.1101/2023.01.25.525462

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.