{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:05:38Z","timestamp":1784261138246,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>HPV DNA-positive women with ASC-US\/LSIL cytology constitute a heterogeneous triage group. We evaluated genotype-specific HPV E6\/E7 mRNA testing with PreTect HPV-Proofer\u20197 in a population-based cohort from Troms\u00f8 and compared the findings descriptively with a previously published cohort from Bod\u00f8. This retrospective quality-assurance study included 1006 HPV DNA-positive women with ASC-US\/LSIL cytology screened between 2019 and 2024, with linkage to regional pathology records through 31 December 2025. The assay detects E6\/E7 mRNA from HPV16, 18, 31, 33, 45, 52, and 58. ASC-US\/LSIL accounted for 42.5% of linked HPV DNA-positive women in Troms\u00f8 compared with 22.3% in Bod\u00f8. Among the mRNA-tested ASC-US\/LSIL cohorts, mRNA positivity was similar (40.8% vs. 44.6%). In Troms\u00f8, CIN2+ was recorded in 26.1% of mRNA-positive and 7.9% of mRNA-negative women (RR 3.31, 95% CI 2.41\u20134.55), whereas CIN3+ was recorded in 3.9% and 1.0%, respectively (RR 3.88, 95% CI 1.53\u20139.82). For CIN2+, sensitivity was 69.5%, specificity 64.4%, PPV 26.1%, and NPV 92.1%. Among HPV16\/18 DNA-positive women, CIN2+ risk was 42.7% in mRNA-positive and 13.4% in mRNA-negative women. Simulated mRNA-guided referral reduced immediate colposcopy referrals by 59.2%. Genotype-specific mRNA testing provided clinically relevant risk stratification, with directionally similar patterns being observed in the Troms\u00f8 and Bod\u00f8 cohorts; however, mRNA-negative women require structured surveillance.<\/jats:p>","DOI":"10.3390\/pathogens15070747","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:12:38Z","timestamp":1784257958000},"page":"747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype-Specific HPV E6\/E7 mRNA Triage for Risk Stratification in HPV DNA-Positive Women with ASC-US\/LSIL: A Population-Based Troms\u00f8 Cohort"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8250-3992","authenticated-orcid":false,"given":"Sveinung Wergeland","family":"S\u00f8rbye","sequence":"first","affiliation":[{"name":"Department of Clinical Pathology, University Hospital of North Norway, 9006 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bente Marie","family":"Falang","sequence":"additional","affiliation":[{"name":"PreTect AS, 3490 Asker, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Antonsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, University Hospital of North Norway, 9006 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3559-7153","authenticated-orcid":false,"given":"Elin","family":"Richardsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, University Hospital of North Norway, 9006 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1470-2045(09)70360-2","article-title":"Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: A randomised controlled trial","volume":"11","author":"Ronco","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.1016\/j.jcv.2015.11.015","article-title":"Triage of HPV positive women in cervical cancer screening","volume":"76","author":"Wentzensen","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/ijc.26056","article-title":"Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening","volume":"130","author":"Rijkaart","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Taghavi, K., Zhao, F., Downham, L., Baena, A., and Basu, P. (2023). Molecular triaging options for women testing HPV positive with self-collected samples. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1243888"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/ijc.31261","article-title":"Eurogin roadmap 2017: Triage strategies for the management of HPV-positive women in cervical screening programs","volume":"143","author":"Cuschieri","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e350","DOI":"10.1016\/S2214-109X(22)00545-9","article-title":"Performance of standardised colposcopy to detect cervical precancer and cancer for triage of women testing positive for human papillomavirus: Results from the ESTAMPA multicentric screening study","volume":"11","author":"Valls","year":"2023","journal-title":"Lancet Glob. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.ejogrb.2020.12.061","article-title":"Options for triage and implications for colposcopists within European HPV-based cervical screening programmes","volume":"258","author":"Leeson","year":"2021","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e70006","DOI":"10.1002\/cncy.70006","article-title":"Extended HPV genotyping and dual stain for the triage of primary HPV screen-positive cases: Practical guidance for the cytopathology laboratory","volume":"133","author":"Goulart","year":"2025","journal-title":"Cancer Cytopathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/LGT.0000000000000525","article-title":"2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors","volume":"24","author":"Perkins","year":"2020","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1001\/jama.285.11.1500","article-title":"Interobserver reproducibility of cervical cytologic and histologic interpretations: Realistic estimates from the ASCUS-LSIL Triage Study","volume":"285","author":"Stoler","year":"2001","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.3802\/jgo.2018.29.e55","article-title":"Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: A population-based cohort study","volume":"29","author":"Tai","year":"2018","journal-title":"J. Gynecol. Oncol."},{"key":"ref_12","first-page":"727","article-title":"Natural history of cervical squamous intraepithelial lesions: A meta-analysis","volume":"92","author":"Melnikow","year":"1998","journal-title":"Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1002\/ijc.28514","article-title":"Interlaboratory variation in the performance of liquid-based cytology: Insights from the ATHENA trial","volume":"134","author":"Wright","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1038\/s41416-020-0790-1","article-title":"Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening","volume":"122","author":"Hashim","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1002\/cncy.22624","article-title":"Inter- and intraobserver agreement in whole-slide digital ThinPrep samples of low-grade squamous lesions of the cervix uteri with known high-risk HPV status: A multicentric international study","volume":"130","author":"Negri","year":"2022","journal-title":"Cancer Cytopathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Simms, K.T., Hall, M., Smith, M.A., Lew, J.-B., Hughes, S., Yuill, S., Hammond, I., Saville, M., and Canfell, K. (2017). Optimal management strategies for primary HPV testing for cervical screening: Cost-effectiveness evaluation for the National Cervical Screening Program in Australia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0163509"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.ygyno.2020.12.038","article-title":"Reducing unnecessary referrals for colposcopy in HPV-positive women within the Dutch cervical cancer screening programme: A modelling study","volume":"160","author":"Kaljouw","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"k4823","DOI":"10.1136\/bmj.k4823","article-title":"Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: Updated meta-analyses","volume":"363","author":"Arbyn","year":"2018","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1136\/jcp.55.6.435","article-title":"Primary screening for high-risk HPV by home-obtained cervicovaginal lavage is an alternative screening tool for unscreened women","volume":"55","author":"Nobbenhuis","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.3332\/ecancer.2020.1138","article-title":"Adherence to triage among women with HPV-positive self-collection: A study in a middle-low income population in Argentina","volume":"14","author":"Paolino","year":"2020","journal-title":"ecancermedicalscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1097\/LGT.0000000000000865","article-title":"Applying results of extended genotyping to management of positive cervicovaginal human papillomavirus test results: Enduring guidelines","volume":"29","author":"Massad","year":"2025","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1128\/JCM.01863-08","article-title":"Performance of human papillomavirus DNA and mRNA testing strategies for women with and without cervical neoplasia","volume":"47","author":"Eskild","year":"2009","journal-title":"J. Clin. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/jmp4020008","article-title":"Performance of a 7-type HPV mRNA test in triage of HPV DNA primary screen-positive women compared with liquid-based cytology","volume":"4","author":"Falang","year":"2023","journal-title":"J. Mol. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/cam4.1961","article-title":"Human papillomavirus types in cervical high-grade lesions or cancer among Nordic women\u2014Potential for prevention","volume":"8","author":"Guleria","year":"2019","journal-title":"Cancer Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1750-9378-7-38","article-title":"Potential impact of a nine-valent vaccine in human papillomavirus-related cervical disease","volume":"7","author":"Serrano","year":"2012","journal-title":"Infect. Agents Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/ijc.20839","article-title":"Predicting CIN2+ when detecting HPV mRNA and DNA by PreTect HPV-Proofer and consensus PCR: A 2-year follow-up of women with ASCUS or LSIL Pap smear","volume":"114","author":"Molden","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S1470-2045(22)00294-7","article-title":"Accuracy and effectiveness of HPV mRNA testing in cervical cancer screening: A systematic review and meta-analysis","volume":"23","author":"Arbyn","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1128\/JCM.02570-10","article-title":"Sensitivity, specificity, and clinical value of human papillomavirus E6\/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test","volume":"49","author":"Benevolo","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Al-Shibli, K., Nguyen, D.T., Mohammed, H.A.L., and S\u00f8rbye, S.W. (2026). Genotype-specific HPV E6\/E7 mRNA triage improves risk stratification and reduces referrals in DNA-positive ASC-US\/LSIL: A real-world cohort from Nordland, Norway. Pathogens, 15.","DOI":"10.3390\/pathogens15020178"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"S\u00f8rbye, S., Falang, B.M., Antonsen, M., and Mortensen, E. (2025). Genotype-specific HPV mRNA triage improves CIN2+ detection efficiency compared to cytology: A population-based study of HPV DNA-positive women. Pathogens, 14.","DOI":"10.20944\/preprints202506.2527.v1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"S\u00f8rbye, S.W., Falang, B.M., Antonsen, M., and Richardsen, E. (2026). Genotype-specific HPV mRNA triage improves colposcopy efficiency compared with cytology and ATHENA-derived triage: A population-based study of HPV DNA-positive women. Pathogens, 15.","DOI":"10.3390\/pathogens15060584"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Johansson, H., Bjelkenkrantz, K., Darlin, L., Dillner, J., and Forslund, O. (2015). Presence of high-risk HPV mRNA in relation to future high-grade lesions among high-risk HPV DNA positive women with minor cytological abnormalities. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124460"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1017\/S0950268818000250","article-title":"A prospective study of women with ASCUS or LSIL Pap smears at baseline and HPV E6\/E7 mRNA positive: A 3-year follow-up","volume":"146","author":"Bruno","year":"2018","journal-title":"Epidemiol. Infect."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhang, J., Yang, D., Cui, X., Liu, G., Cui, Z., Wang, C., and Piao, H. (2022). Performance of human papillomavirus E6\/E7 mRNA assay for primary cervical cancer screening and triage: Population-based screening in China. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.935071"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104009","DOI":"10.1016\/j.eclinm.2026.104009","article-title":"Accuracy of colposcopy to triage HPV-positive women in cervical cancer screening: A systematic review and meta-analysis","volume":"96","author":"Dhollander","year":"2026","journal-title":"eClinicalMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Aranda Flores, C.E., Falang, B.M., G\u00f3mez-Laguna, L., Guti\u00e9rrez, G.G., Le\u00f3n, J.M.O., Uribe, M., Cruz, O., and S\u00f8rbye, S.W. (2024). Enhancing cervical cancer screening with 7-type HPV mRNA E6\/E7 testing on self-collected samples: Multicentric insights from Mexico. Cancers, 16.","DOI":"10.3390\/cancers16132485"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/7\/747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:44:53Z","timestamp":1784259893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/7\/747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pathogens15070747"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15070747","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}