Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Martin S. Taylor; Connie Wu; Peter C. Fridy; Stephanie J. Zhang; Yasmeen Senussi; Justina C. Wolters; Tatiana Cajuso; Wen Chih Cheng; John D. Heaps; Bryant D. Miller; Kei Mori; Limor Cohen; Hua Jiang; Kelly R. Molloy; Brian T. Chait; Michael G. Goggins; Irun Bhan; Joseph W. Franses; Xiaoyu Yang; Mary Ellen Taplin; Xinan Wang; David C. Christiani; Bruce E. Johnson; Matthew Meyerson; Ravindra Uppaluri; Ann Marie Egloff; Elyssa N. Denault; Laura M. Spring; Tian Li Wang; Ie Ming Shih; Jennifer E. Fairman; Euihye Jung; Kshitij S. Arora; Osman H. Yilmaz; Sonia Cohen; Tatyana Sharova; Gary Chi; Bryanna L. Norden; Yuhui Song; Linda T. Nieman; Leontios Pappas; Aparna R. Parikh; Matthew R. Strickland; Ryan B. Corcoran; Tomas Mustelin; George Eng; Ömer H. Yilmaz; Ursula A. Matulonis; Andrew T. Chan; Steven J. Skates; Bo R. Rueda; Ronny Drapkin; Samuel J. Klempner; Vikram Deshpande; David T. Ting; Michael P. Rout; John Lacava; David R. Walt; Kathleen H. Burns

doi:10.1158/2159-8290.CD-23-0313

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Martin S. Taylor, Connie Wu, Peter C. Fridy, Stephanie J. Zhang, Yasmeen Senussi, Justina C. Wolters, Tatiana Cajuso, Wen Chih Cheng, John D. Heaps, Bryant D. Miller, Kei Mori, Limor Cohen, Hua Jiang, Kelly R. Molloy, Brian T. Chait, Michael G. Goggins, Irun Bhan, Joseph W. Franses, Xiaoyu Yang, Mary Ellen TaplinXinan Wang, David C. Christiani, Bruce E. Johnson, Matthew Meyerson, Ravindra Uppaluri, Ann Marie Egloff, Elyssa N. Denault, Laura M. Spring, Tian Li Wang, Ie Ming Shih, Jennifer E. Fairman, Euihye Jung, Kshitij S. Arora, Osman H. Yilmaz, Sonia Cohen, Tatyana Sharova, Gary Chi, Bryanna L. Norden, Yuhui Song, Linda T. Nieman, Leontios Pappas, Aparna R. Parikh, Matthew R. Strickland, Ryan B. Corcoran, Tomas Mustelin, George Eng, Ömer H. Yilmaz, Ursula A. Matulonis, Andrew T. Chan, Steven J. Skates, Bo R. Rueda, Ronny Drapkin, Samuel J. Klempner, Vikram Deshpande, David T. Ting, Michael P. Rout, John Lacava, David R. Walt, Kathleen H. Burns

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10⁻¹⁷ mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is 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 μL plasma are novel, rapid, costeffective tools in cancer detection and monitoring.

Original language	English (US)
Pages (from-to)	2532-2547
Number of pages	16
Journal	Cancer discovery
Volume	13
Issue number	12
DOIs	https://doi.org/10.1158/2159-8290.CD-23-0313
State	Published - Dec 1 2023

ASJC Scopus subject areas

Oncology

Access to Document

10.1158/2159-8290.CD-23-0313

Cite this

Taylor, M. S., Wu, C., Fridy, P. C., Zhang, S. J., Senussi, Y., Wolters, J. C., Cajuso, T., Cheng, W. C., Heaps, J. D., Miller, B. D., Mori, K., Cohen, L., Jiang, H., Molloy, K. R., Chait, B. T., Goggins, M. G., Bhan, I., Franses, J. W., Yang, X., ... Burns, K. H. (2023). Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker. Cancer discovery, 13(12), 2532-2547. https://doi.org/10.1158/2159-8290.CD-23-0313

Taylor, MS, Wu, C, Fridy, PC, Zhang, SJ, Senussi, Y, Wolters, JC, Cajuso, T, Cheng, WC, Heaps, JD, Miller, BD, Mori, K, Cohen, L, Jiang, H, Molloy, KR, Chait, BT, Goggins, MG, Bhan, I, Franses, JW, Yang, X, Taplin, ME, Wang, X, Christiani, DC, Johnson, BE, Meyerson, M, Uppaluri, R, Egloff, AM, Denault, EN, Spring, LM, Wang, TL , Shih, IM , Fairman, JE, Jung, E, Arora, KS, Yilmaz, OH, Cohen, S, Sharova, T, Chi, G, Norden, BL, Song, Y, Nieman, LT, Pappas, L, Parikh, AR, Strickland, MR, Corcoran, RB, Mustelin, T, Eng, G, Yilmaz, ÖH, Matulonis, UA, Chan, AT, Skates, SJ, Rueda, BR, Drapkin, R, Klempner, SJ, Deshpande, V, Ting, DT, Rout, MP, Lacava, J, Walt, DR & Burns, KH 2023, 'Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker', Cancer discovery, vol. 13, no. 12, pp. 2532-2547. https://doi.org/10.1158/2159-8290.CD-23-0313

@article{73a8d18cd6544f7ca1e3e59e5d4ee347,

title = "Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker",

abstract = "Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is 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 μL plasma are novel, rapid, costeffective tools in cancer detection and monitoring.",

author = "Taylor, {Martin S.} and Connie Wu and Fridy, {Peter C.} and Zhang, {Stephanie J.} and Yasmeen Senussi and Wolters, {Justina C.} and Tatiana Cajuso and Cheng, {Wen Chih} and Heaps, {John D.} and Miller, {Bryant D.} and Kei Mori and Limor Cohen and Hua Jiang and Molloy, {Kelly R.} and Chait, {Brian T.} and Goggins, {Michael G.} and Irun Bhan and Franses, {Joseph W.} and Xiaoyu Yang and Taplin, {Mary Ellen} and Xinan Wang and Christiani, {David C.} and Johnson, {Bruce E.} and Matthew Meyerson and Ravindra Uppaluri and Egloff, {Ann Marie} and Denault, {Elyssa N.} and Spring, {Laura M.} and Wang, {Tian Li} and Shih, {Ie Ming} and Fairman, {Jennifer E.} and Euihye Jung and Arora, {Kshitij S.} and Yilmaz, {Osman H.} and Sonia Cohen and Tatyana Sharova and Gary Chi and Norden, {Bryanna L.} and Yuhui Song and Nieman, {Linda T.} and Leontios Pappas and Parikh, {Aparna R.} and Strickland, {Matthew R.} and Corcoran, {Ryan B.} and Tomas Mustelin and George Eng and Yilmaz, {{\"O}mer H.} and Matulonis, {Ursula A.} and Chan, {Andrew T.} and Skates, {Steven J.} and Rueda, {Bo R.} and Ronny Drapkin and Klempner, {Samuel J.} and Vikram Deshpande and Ting, {David T.} and Rout, {Michael P.} and John Lacava and Walt, {David R.} and Burns, {Kathleen H.}",

note = "Publisher Copyright: {\textcopyright}2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = dec,

day = "1",

doi = "10.1158/2159-8290.CD-23-0313",

language = "English (US)",

volume = "13",

pages = "2532--2547",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

TY - JOUR

T1 - Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

AU - Taylor, Martin S.

AU - Wu, Connie

AU - Fridy, Peter C.

AU - Zhang, Stephanie J.

AU - Senussi, Yasmeen

AU - Wolters, Justina C.

AU - Cajuso, Tatiana

AU - Cheng, Wen Chih

AU - Heaps, John D.

AU - Miller, Bryant D.

AU - Mori, Kei

AU - Cohen, Limor

AU - Jiang, Hua

AU - Molloy, Kelly R.

AU - Chait, Brian T.

AU - Goggins, Michael G.

AU - Bhan, Irun

AU - Franses, Joseph W.

AU - Yang, Xiaoyu

AU - Taplin, Mary Ellen

AU - Wang, Xinan

AU - Christiani, David C.

AU - Johnson, Bruce E.

AU - Meyerson, Matthew

AU - Uppaluri, Ravindra

AU - Egloff, Ann Marie

AU - Denault, Elyssa N.

AU - Spring, Laura M.

AU - Wang, Tian Li

AU - Shih, Ie Ming

AU - Fairman, Jennifer E.

AU - Jung, Euihye

AU - Arora, Kshitij S.

AU - Yilmaz, Osman H.

AU - Cohen, Sonia

AU - Sharova, Tatyana

AU - Chi, Gary

AU - Norden, Bryanna L.

AU - Song, Yuhui

AU - Nieman, Linda T.

AU - Pappas, Leontios

AU - Parikh, Aparna R.

AU - Strickland, Matthew R.

AU - Corcoran, Ryan B.

AU - Mustelin, Tomas

AU - Eng, George

AU - Yilmaz, Ömer H.

AU - Matulonis, Ursula A.

AU - Chan, Andrew T.

AU - Skates, Steven J.

AU - Rueda, Bo R.

AU - Drapkin, Ronny

AU - Klempner, Samuel J.

AU - Deshpande, Vikram

AU - Ting, David T.

AU - Rout, Michael P.

AU - Lacava, John

AU - Walt, David R.

AU - Burns, Kathleen H.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is 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 μL plasma are novel, rapid, costeffective tools in cancer detection and monitoring.

AB - Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is 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 μL plasma are novel, rapid, costeffective tools in cancer detection and monitoring.

UR - http://www.scopus.com/inward/record.url?scp=85177463805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85177463805&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-23-0313

DO - 10.1158/2159-8290.CD-23-0313

M3 - Article

C2 - 37698949

AN - SCOPUS:85177463805

SN - 2159-8274

VL - 13

SP - 2532

EP - 2547

JO - Cancer discovery

JF - Cancer discovery

IS - 12

ER -

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this