Dataset Information

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, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489.

SUBMITTER: Taylor MS

PROVIDER: S-EPMC10773488 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Taylor Martin S MS Wu Connie C Fridy Peter C PC Zhang Stephanie J SJ Senussi Yasmeen Y Wolters Justina C JC Cajuso Tatiana T Cheng Wen-Chih WC Heaps John D JD Miller Bryant D BD Mori Kei K Cohen Limor L Jiang Hua H Molloy Kelly R KR Chait Brian T BT Goggins Michael G MG Bhan Irun I Franses Joseph W JW Yang Xiaoyu X Taplin Mary-Ellen ME Wang Xinan X Christiani David C DC Johnson Bruce E BE Meyerson Matthew M Uppaluri Ravindra R Egloff Ann Marie AM Denault Elyssa N EN Spring Laura M LM Wang Tian-Li TL Shih Ie-Ming IM Fairman Jennifer E JE Jung Euihye E Arora Kshitij S KS Yilmaz Osman H OH Cohen Sonia S Sharova Tatyana T Chi Gary G Norden Bryanna L BL Song Yuhui Y Nieman Linda T LT Pappas Leontios L Parikh Aparna R AR Strickland Matthew R MR Corcoran Ryan B RB Mustelin Tomas T Eng George G Yilmaz Ömer H ÖH Matulonis Ursula A UA Chan Andrew T AT Skates Steven J SJ Rueda Bo R BR Drapkin Ronny R Klempner Samuel J SJ Deshpande Vikram V Ting David T DT Rout Michael P MP LaCava John J Walt David R DR Burns Kathleen H KH

Cancer discovery 20231201 12

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 ...[more]

PMID: 37698949

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Project description:PurposeHuman papillomavirus (HPV) DNA offers a convenient circulating tumor DNA (ctDNA) marker for HPV-associated malignancies, but current methods, such as digital PCR (dPCR), provide insufficient accuracy for clinical applications in patients with low disease burden. We asked whether a next-generation sequencing approach, HPV sequencing (HPV-seq), could provide quantitative and qualitative assessment of HPV ctDNA in low disease burden settings.Experimental designWe conducted preclinical technical validation studies on HPV-seq and applied it retrospectively to a prospective multicenter cohort of patients with locally advanced cervix cancer (NCT02388698) and a cohort of patients with oropharynx cancer. HPV-seq results were compared with dPCR. The primary outcome was progression-free survival (PFS) according to end-of-treatment HPV ctDNA detectability.ResultsHPV-seq achieved reproducible detection of HPV DNA at levels less than 0.6 copies in cell line data. HPV-seq and dPCR results for patients were highly correlated (R 2 = 0.95, P = 1.9 × 10-29) with HPV-seq detecting ctDNA at levels down to 0.03 copies/mL plasma in dPCR-negative posttreatment samples. Detectable HPV ctDNA at end-of-treatment was associated with inferior PFS with 100% sensitivity and 67% specificity for recurrence. Accurate HPV genotyping was successful from 100% of pretreatment samples. HPV ctDNA fragment sizes were consistently shorter than non-cancer-derived cell-free DNA (cfDNA) fragments, and stereotyped cfDNA fragmentomic patterns were observed across HPV genomes.ConclusionsHPV-seq is a quantitative method for ctDNA detection that outperforms dPCR and reveals qualitative information about ctDNA. Our findings in this proof-of-principle study could have implications for treatment monitoring of disease burden in HPV-related cancers. Future prospective studies are needed to confirm that patients with undetectable HPV ctDNA following chemoradiotherapy have exceptionally high cure rates.

Dataset Information

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

Significance

Publications

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

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