TY - JOUR
T1 - Genome-wide microRNA analysis of HPV-positive self-samples yields novel triage markers for early detection of cervical cancer
AU - Snoek, Barbara C.
AU - Verlaat, Wina
AU - Babion, Iris
AU - Novianti, Putri W.
AU - van de Wiel, Mark A.
AU - Wilting, Saskia M.
AU - van Trommel, Nienke E.
AU - Bleeker, Maaike C.G.
AU - Massuger, Leon F.A.G.
AU - Melchers, Willem J.G.
AU - Sie, Daoud
AU - Heideman, Daniëlle A.M.
AU - Snijders, Peter J.F.
AU - Meijer, Chris J.L.M.
AU - Steenbergen, Renske D.M.
N1 - Funding Information: The authors thank Paul Eijk for excellent technical assistance. D. Heideman, P. Snijders, C. Meijer and R. Steenbergen have a minority stake in Self-screen B.V., a spin-off company of Amsterdam UMC (formerly known as VU University Medical Center Amsterdam), which owns patents related to this work. D. Heideman has been on the speaker's bureau of Qiagen, and serves occasionally on the scientific advisory board of Pfizer and Bristol-Meyer Squibb. P. Snijders has been on the speaker's bureau of Roche, Abbott, Gen-Probe, Qiagen, and Seegene, and was a consultant for Crucell Holland B.V. C. Meijer has participated in the sponsored speaker's bureau of SPMSD/Merck, and served occasionally on the scientific advisory board of Qiagen and SPMSD/Merck. He was coinvestigator on a SPMSD sponsored HPV vaccination trial of which his institute received research funding, and was a minority shareholder of Diassay B.V till March 2016. He owns a very small number of Qiagen shares and is part time director of Self-Screen. All other authors declare that they have no competing interests. Publisher Copyright: © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - Offering self-sampling for HPV testing improves the effectiveness of current cervical screening programs by increasing population coverage. Molecular markers directly applicable on self-samples are needed to stratify HPV-positive women at risk of cervical cancer (so-called triage) and to avoid over-referral and overtreatment. Deregulated microRNAs (miRNAs) have been implicated in the development of cervical cancer, and represent potential triage markers. However, it is unknown whether deregulated miRNA expression is reflected in self-samples. Our study is the first to establish genome-wide miRNA profiles in HPV-positive self-samples to identify miRNAs that can predict the presence of CIN3 and cervical cancer in self-samples. Small RNA sequencing (sRNA-Seq) was conducted to determine genome-wide miRNA expression profiles in 74 HPV-positive self-samples of women with and without cervical precancer (CIN3). The optimal miRNA marker panel for CIN3 detection was determined by GRridge, a penalized method on logistic regression. Six miRNAs were validated by qPCR in 191 independent HPV-positive self-samples. Classification of sRNA-Seq data yielded a 9-miRNA marker panel with a combined area under the curve (AUC) of 0.89 for CIN3 detection. Validation by qPCR resulted in a combined AUC of 0.78 for CIN3+ detection. Our study shows that deregulated miRNA expression associated with CIN3 and cervical cancer development can be detected by sRNA-Seq in HPV-positive self-samples. Validation by qPCR indicates that miRNA expression analysis offers a promising novel molecular triage strategy for CIN3 and cervical cancer detection applicable to self-samples.
AB - Offering self-sampling for HPV testing improves the effectiveness of current cervical screening programs by increasing population coverage. Molecular markers directly applicable on self-samples are needed to stratify HPV-positive women at risk of cervical cancer (so-called triage) and to avoid over-referral and overtreatment. Deregulated microRNAs (miRNAs) have been implicated in the development of cervical cancer, and represent potential triage markers. However, it is unknown whether deregulated miRNA expression is reflected in self-samples. Our study is the first to establish genome-wide miRNA profiles in HPV-positive self-samples to identify miRNAs that can predict the presence of CIN3 and cervical cancer in self-samples. Small RNA sequencing (sRNA-Seq) was conducted to determine genome-wide miRNA expression profiles in 74 HPV-positive self-samples of women with and without cervical precancer (CIN3). The optimal miRNA marker panel for CIN3 detection was determined by GRridge, a penalized method on logistic regression. Six miRNAs were validated by qPCR in 191 independent HPV-positive self-samples. Classification of sRNA-Seq data yielded a 9-miRNA marker panel with a combined area under the curve (AUC) of 0.89 for CIN3 detection. Validation by qPCR resulted in a combined AUC of 0.78 for CIN3+ detection. Our study shows that deregulated miRNA expression associated with CIN3 and cervical cancer development can be detected by sRNA-Seq in HPV-positive self-samples. Validation by qPCR indicates that miRNA expression analysis offers a promising novel molecular triage strategy for CIN3 and cervical cancer detection applicable to self-samples.
KW - cervical intraepithelial neoplasia
KW - human papillomavirus
KW - microRNA profiling
KW - self-sampling
UR - http://www.scopus.com/inward/record.url?scp=85056152504&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.31855
DO - https://doi.org/10.1002/ijc.31855
M3 - Article
C2 - 30192375
SN - 0020-7136
VL - 144
SP - 372
EP - 379
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -