Evidence map›Paper›PMID 34321221›Full record

ArticleGut2021

Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer.

Johann von Felden, Teresa Garcia-Lezana, Navneet Dogra, Edgar Gonzalez-Kozlova, Mehmet Eren Ahsen, Amanda Craig, Stacey Gifford, Benjamin Wunsch, Joshua T Smith, Sungcheol Kim and 22 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gut, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed, 2 pooled it
3.9field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed, 2 syntheses or guidelines pooled it, 58 citations in OpenAlex.

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  11. [Research advances in occurrence risk assessment and early-stage diagnosis of hepatocellular carcinoma].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

32 authors at 7 institutions in 4 countries.

Johann von FeldenDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.ORCID http://orcid.org/0000-0003-2839-5174
Teresa Garcia-LezanaDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Navneet DograDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Edgar Gonzalez-KozlovaDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Mehmet Eren AhsenDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Amanda CraigDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Stacey GiffordIBM Thomas J Watson Research Center, Yorktown Heights, New York, USA.
Benjamin WunschIBM Thomas J Watson Research Center, Yorktown Heights, New York, USA.
Joshua T SmithIBM Thomas J Watson Research Center, Yorktown Heights, New York, USA.
Sungcheol KimIBM Thomas J Watson Research Center, Yorktown Heights, New York, USA.
Jennifer E L DiazDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Xintong ChenDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ismail LabgaaDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.ORCID http://orcid.org/0000-0003-4286-2170
Philipp HaberDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Reena OlsenDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Dan HanDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Paula RestrepoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Delia D'AvolaDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Gabriela Hernandez-MezaDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Kimaada AlletteDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Robert SebraDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Behnam SaberiDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Parissa TabrizianRecanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.ORCID http://orcid.org/0000-0002-7881-7497
Amon AsgharpourDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Douglas DieterichDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Josep M LlovetDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Carlos Cordon-CardoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ash TewariDepartment of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Myron SchwartzDepartment of Surgery, Mount Sinai School of Medicine, New York, New York, USA.
Gustavo StolovitzkyDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA augusto.villanueva@mssm.edu gustavo.stolovitzky@sema4.com blosic@gmail.com.
Bojan LosicDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA augusto.villanueva@mssm.edu gustavo.stolovitzky@sema4.com blosic@gmail.com.
Augusto VillanuevaDivision of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA augusto.villanueva@mssm.edu gustavo.stolovitzky@sema4.com blosic@gmail.com.ORCID http://orcid.org/0000-0003-3585-3727
Icahn School of Medicine at Mount Sinai · USIBM Research - Thomas J. Watson Research Center · USCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · ESInstitució Catalana de Recerca i Estudis Avançats · ESSema4 (United States) · USUniversität Hamburg · DEUniversity of Lausanne · CH

Funding

Scientific ReagentsP01CA087497 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI PRIVES, CAROL · 2000 to 2021
$35.4M
TRAINING PROGRAM IN CANCER THERAPYT32CA078207 · NCI · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI James J Manfredi · 1999 to 2026
$11.6M
A New Disease Platform Leveraging Complex Drosophila and Mammalian ModelsU54OD020353 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI CAGAN, ROSS LEIGH · 2015 to 2019
$10.3M
NCI NIH HHS P01 CA087497NCI NIH HHS T32 CA078207NIH HHS U54 OD020353
6 · The paper itself

Abstract

objectiveSurveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions.

designEVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study.

resultsExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93.

conclusionThese findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

Indexed as

cancer preventiongene expressionhepatobiliary cancersurveillancetumour markers

Identifiers

PMID34321221
PMCPMC8795201
OpenAlexW3185328556

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.