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

Taylor, M. S.; Connie, W.; Fridy, P. C.; Senussi, Y.; Cheng, W.-C.; Heaps, J.; Mori, K.; Cohen, L.; Molloy, K. R.; Chait, B. T.; Goggins, M.; Bhan, I.; Franses, J. W.; Yang, X.; Taplin, M.-E.; Wang, X.; Christiani, D. C.; Johnson, B. E.; Meyerson, M.; Uppaluri, R.; Egloff, A. M.; Denault, E. N.; Spring, L. M.; Wang, T.-L.; Shih, I.-M.; Jung, E.; Arora, K. S.; Zukerberg, L. R.; Yilmaz, O. H.; Chi, G.; Norden, B. L.; Song, Y.; Nieman, L.; Parikh, A. R.; Strickland, M.; Mustelin, T.; Eng, G.; Matulonis, U. A.; Skates, S. J.; Rueda, B. R.; Drapkin, R.; Klempner, S. J.; Deshpande, V.

doi:10.1101/2023.01.25.525462

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bioRxiv · 10.1101/2023.01.25.525462

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

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Abstract

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. Statement of SignificanceLINE-1 ORF1p transposon protein is pervasively expressed in many cancers and a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 L plasma are novel, rapid, cost-effective tools in cancer detection and monitoring.

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Taylor, M. S., Connie, W., Fridy, P. C., Senussi, Y., Cheng, W.-C., Heaps, J., Mori, K., Cohen, L., Molloy, K. R., Chait, B. T., Goggins, M., Bhan, I., Franses, J. W., Yang, X., Taplin, M.-E., Wang, X., Christiani, D. C., Johnson, B. E., Meyerson, M., Uppaluri, R., Egloff, A. M., Denault, E. N., Spring, L. M., Wang, T.-L., Shih, I.-M., Jung, E., Arora, K. S., Zukerberg, L. R., Yilmaz, O. H., Chi, G., Norden, B. L., Song, Y., Nieman, L., Parikh, A. R., Strickland, M., Mustelin, T., Eng, G., Matulonis, U. A., Skates, S. J., Rueda, B. R., Drapkin, R., Klempner, S. J., Deshpande, V.. 2023-01-25. Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker. https://doi.org/10.1101/2023.01.25.525462

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