Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer
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Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer. / von Felden, Johann; Garcia-Lezana, Teresa; Dogra, Navneet; Gonzalez-Kozlova, Edgar; Ahsen, Mehmet Eren; Craig, Amanda; Gifford, Stacey; Wunsch, Benjamin; Smith, Joshua T; Kim, Sungcheol; Diaz, Jennifer E L; Chen, Xintong; Labgaa, Ismail; Haber, Philipp; Olsen, Reena; Han, Dan; Restrepo, Paula; D'Avola, Delia; Hernandez-Meza, Gabriela; Allette, Kimaada; Sebra, Robert; Saberi, Behnam; Tabrizian, Parissa; Asgharpour, Amon; Dieterich, Douglas; Llovet, Josep M; Cordon-Cardo, Carlos; Tewari, Ash; Schwartz, Myron; Stolovitzky, Gustavo; Losic, Bojan; Villanueva, Augusto.
in: GUT, Jahrgang 71, Nr. 10, 07.2022, S. 2069-2080.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer
AU - von Felden, Johann
AU - Garcia-Lezana, Teresa
AU - Dogra, Navneet
AU - Gonzalez-Kozlova, Edgar
AU - Ahsen, Mehmet Eren
AU - Craig, Amanda
AU - Gifford, Stacey
AU - Wunsch, Benjamin
AU - Smith, Joshua T
AU - Kim, Sungcheol
AU - Diaz, Jennifer E L
AU - Chen, Xintong
AU - Labgaa, Ismail
AU - Haber, Philipp
AU - Olsen, Reena
AU - Han, Dan
AU - Restrepo, Paula
AU - D'Avola, Delia
AU - Hernandez-Meza, Gabriela
AU - Allette, Kimaada
AU - Sebra, Robert
AU - Saberi, Behnam
AU - Tabrizian, Parissa
AU - Asgharpour, Amon
AU - Dieterich, Douglas
AU - Llovet, Josep M
AU - Cordon-Cardo, Carlos
AU - Tewari, Ash
AU - Schwartz, Myron
AU - Stolovitzky, Gustavo
AU - Losic, Bojan
AU - Villanueva, Augusto
N1 - © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/7
Y1 - 2022/7
N2 - OBJECTIVE: Surveillance 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.DESIGN: EVs 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.RESULTS: ExRNA 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.CONCLUSION: These 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.
AB - OBJECTIVE: Surveillance 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.DESIGN: EVs 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.RESULTS: ExRNA 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.CONCLUSION: These 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.
U2 - 10.1136/gutjnl-2021-325036
DO - 10.1136/gutjnl-2021-325036
M3 - SCORING: Journal article
C2 - 34321221
VL - 71
SP - 2069
EP - 2080
JO - GUT
JF - GUT
SN - 0017-5749
IS - 10
ER -
