Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for pancreatic and colorectal adenocarcinoma.
Improved non-invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non-coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as biomarkers for non-invasive cancer diagnosis. Analyzing serum derived from nude mice implanted with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR-1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR-1246 assays with RNA fragments derived from U2 small nuclear RNA (RNU2-1). Importantly, we found that the assay signal discriminating tumor from controls was derived from U2 small nuclear RNA (snRNA) fragments (RNU2-1f) and not from miR-1246. In addition, we observed a remarkable stability of RNU2-1f in serum and provide experimental evidence that hsa-miR-1246 is likely a pseudo microRNA. In a next step, RNU2-1f was measured by qRT-PCR and normalized to cel-54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity and specificity of 97.7% [95% CI = (87.7, 99.9)] and 90.6% [95% CI = (80.7, 96.5)], respectively [area under the ROC curve 0.972]. Of note, patients with CRC were detected with our assay as early as UICC Stage II with a sensitivity of 81%. In conclusion, this is the first report showing that fragments of U2 snRNA are highly stable in serum and plasma and may serve as novel diagnostic biomarker for PDAC and CRC for future prospective screening studies.
Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
Alexander
A
Baraniskin
Stefanie
S
Nöpel-Dünnebacke
Maike
M
Ahrens
Steffen Grann
SG
Jensen
Hannah
H
Zöllner
Abdelouahid
A
Maghnouj
Alexandra
A
Wos
Julia
J
Mayerle
Johanna
J
Munding
Dennis
D
Kost
Anke
A
Reinacher-Schick
Sven
S
Liffers
Roland
R
Schroers
Ansgar M
AM
Chromik
Helmut E
HE
Meyer
Waldemar
W
Uhl
Susanne
S
Klein-Scory
Frank U
FU
Weiss
Christian
C
Stephan
Irmgard
I
Schwarte-Waldhoff
Markus M
MM
Lerch
Andrea
A
Tannapfel
Wolff
W
Schmiegel
Claus Lindbjerg
CL
Andersen
Stephan A
SA
Hahn
D000230:Adenocarcinoma / Q000097:blood* / Q000175:diagnosis; D000818:Animals; D017209:Apoptosis; D019540:Area Under Curve; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000097:blood*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000175:diagnosis; D020871:RNA Stability; D012342:RNA, Small Nuclear / Q000097:blood*; D012372:ROC Curve; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C577700:MIRN1246 microRNA, human; D035683:MicroRNAs; D012342:RNA, Small Nuclear; C405484:U2 small nuclear RNA