Effective methylation triage of HPV positive women with abnormal cytology in a middle-income country.
Adult
Aged
Atypical Squamous Cells of the Cervix
/ pathology
Colombia
DNA Methylation
Early Detection of Cancer
/ methods
Female
Genes, Viral
/ genetics
Humans
Middle Aged
Papillomavirus Infections
/ complications
Sensitivity and Specificity
Uterine Cervical Neoplasms
/ diagnosis
Uterine Cervical Dysplasia
/ diagnosis
DNA methylation
HPV test
biomarkers
cervical cancer
triage
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 03 2021
15 03 2021
Historique:
received:
24
04
2020
revised:
20
07
2020
accepted:
24
08
2020
pubmed:
3
10
2020
medline:
20
7
2021
entrez:
2
10
2020
Statut:
ppublish
Résumé
The S5-methylation test, an alternative to cytology and HPV16/18 genotyping to triage high-risk HPV-positive (hrHPV+) women, has not been widely validated in low-middle-income countries (LMICs). We compared S5 to HPV16/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier-borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183 <CIN2 hrHPV+. Baseline specimens were HPV-genotyped and tested by S5-methylation, blinded to cytology, histology and initial HPV results. We evaluated the test performance of predefined S5-classifier (cut-point 0.8) and a post hoc classifier at a different cut-point (3.1). S5 sensitivity for CIN2+ was 82% (95% confidence interval [CI] 76.4-87.5) and for CIN3+ 77.08% (95% CI 65.19-88.97). S5 sensitivity was higher than HPV16/18 sensitivity (48.1%, 95% CI 40.85-55.33) or cytology (31.21%, 95% CI 24.50-37.93) but with lower specificity (35%, 95% CI 28.1-42). At cut-point 3.1, S5 sensitivity for CIN2+ (55.2%, 95% CI 48-62.4) or CIN3+ (64.6%, 95% CI 51.0-78.1) was also superior to HPV16/18 (P < .05) or cytology (P < .0001). At this cut-point S5 specificity (76%, 95% CI 69.8-82.1 for <CIN2) was higher than HPV16/18 (67.21%, 95% CI 60.41-74.01, P = .0062) and similar to cytology (75.57%, 95% CI 69.34-81.79, P = 1). HPV16/18 plus cytology sensitivity was similar to S5 for CIN3+, however, false-positive rate was higher (50.27% vs. 24.04%). High sensitivity is crucial in LMICs, S5-methylation exceeded HPV16/18 or cytology sensitivity with comparable specificity for CIN2+ and CIN3+ in hrHPV-positive Colombian women. Furthermore, S5 triage had comparable sensitivity and significantly fewer false positives than cytology and HPV16/18 combination.
Types de publication
Journal Article
Pragmatic Clinical Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1383-1393Subventions
Organisme : Cancer Research UK
ID : 16891
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 27046
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C569/A10404
Pays : United Kingdom
Investigateurs
Gloria I Sanchez Pi
(GI)
Armando Baena
(A)
Maria C Agudelo
(MC)
Arianis Tatiana Ramirez
(A)
Kelly Melisa Castañeda
(K)
Mauricio Borrero
(M)
Marcela Riveros
(M)
Astrid Bedoya
(A)
Alejandra Botero
(A)
Catalina Villa
(C)
Victor Florez
(V)
Carolina Lopez
(C)
Maribel Almonte
(M)
Rolando Herrero
(R)
Mark Stoler
(M)
Philip E Castle
(PE)
Peter Sasieni
(P)
Guadalupe Posada
(G)
Luis Jaime Gomez
(L)
Carlos A Buitrago
(CA)
Juan C Ochoa
(JC)
David Suescun
(D)
Claudia Cristina Rivera
(C)
Liliana Gamboa
(L)
Maria Elena Londoño
(M)
Natalia Echeverry
(N)
Ruth Elena Arboleda
(R)
Sandra Herrera
(S)
Maria Eugenia Mejia
(M)
Marleny Valencia
(M)
Lina Toro
(L)
Jhon Henry Osorio
(J)
Jaime Agudelo
(J)
Gustavo Trujillo
(G)
Cristina Jimenez
(C)
Lizeth Ruiz
(L)
Mary Luz Arteaga
(M)
Liliana Rendon
(L)
Lina Serna
(L)
Jose Miguel Abad
(J)
Beatriz Eugenia Perez
(B)
Gloria Cristina Calderon
(GC)
Jaime Alexander Castañeda
(J)
Luz Helena Londoño
(LH)
Lucy Sanchez
(L)
Informations de copyright
© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.
Références
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890-907.
Ghebreyesus TA. Global Call for Action Towards the Elimination of Cervical Cancer. Vol 2019. Geneva, Switzerland: World Health Organization; 2018.
Koliopoulos G, Nyaga VN, Santesso N, et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev. 2017;8:CD008587.
Mezei AK, Armstrong HL, Pedersen HN, et al. Cost-effectiveness of cervical cancer screening methods in low- and middle-income countries: a systematic review. Int J Cancer. 2017;141:437-446.
Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383:524-532.
Rijkaart DC, Berkhof J, van Kemenade FJ, et al. Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening. Int J Cancer. 2012;130:602-610.
Demarco M, Lorey TS, Fetterman B, et al. Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: the Foundation of Risk-Based Cervical Screening Guidelines. J Low Genit Tract Dis. 2017;21:261-267.
Wentzensen N, Clarke MA, Bremer R, et al. Clinical evaluation of human papillomavirus screening with p16/Ki-67 dual stain triage in a large organized cervical cancer screening program. JAMA Intern Med. 2019;179:881-888.
Stanczuk GA, Baxter GJ, Currie H, et al. Defining optimal triage strategies for hrHPV screen-positive women-an evaluation of HPV 16/18 genotyping, cytology, and p16/Ki-67 cytoimmunochemistry. Cancer Epidemiol Biomarkers Prev. 2017;26:1629-1635.
Clarke MA, Wentzensen N, Mirabello L, et al. Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiol Biomarkers Prev. 2012;21:2125-2137.
Vasiljević N, Scibior-Bentkowska D, Brentnall AR, Cuzick J, Lorincz AT. Credentialing of DNA methylation assays for human genes as diagnostic biomarkers of cervical intraepithelial neoplasia in high-risk HPV positive women. Gynecol Oncol. 2014;132:709-714.
Brentnall AR, Vasiljevic N, Scibior-Bentkowska D, et al. HPV33 DNA methylation measurement improves cervical pre-cancer risk estimation of an HPV16, HPV18, HPV31 and EPB41L3 methylation classifier. Cancer Biomark. 2015;15:669-675.
Lorincz AT, Brentnall AR, Scibior-Bentkowska D, et al. Validation of a DNA methylation HPV triage classifier in a screening sample. Int J Cancer. 2016;138:2745-2751.
Cook DA, Krajden M, Brentnall AR, et al. Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial. Int J Cancer. 2019;144:2587-2595.
Hernández-López R, Lorincz AT, Torres-Ibarra L, et al. Methylation estimates the risk of precancer in HPV-infected women with discrepant results between cytology and HPV16/18 genotyping. Clin Epigenetics. 2019;11:140.
Baena A, Agudelo M, Lopez C, et al. Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: the ASCUS-COL trial. Int J Cancer. 2020.
Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol. 2000;38:357-361.
Santos NP, Ribeiro-Rodrigues EM, Ribeiro-Dos-Santos AK, et al. Assessing individual interethnic admixture and population substructure using a 48-insertion-deletion (INSEL) ancestry-informative marker (AIM) panel. Hum Mutat. 2010;31:184-190.
Bonde J, Ejegod DM, Cuschieri K, et al. The Valgent4 protocol: robust analytical and clinical validation of 11 HPV assays with genotyping on cervical samples collected in SurePath medium. J Clin Virol. 2018;108:64-71.
DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837-845.
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2016.
World Health Organization. WHO guidelines for the use of thermal ablation for cervical pre-cancer lesions; 2019.
Lazcano-Ponce E, Lorincz AT, Cruz-Valdez A, et al. Self-collection of vaginal specimens for human papillomavirus testing in cervical cancer prevention (MARCH): a community-based randomised controlled trial. Lancet. 2011;378:1868-1873.
Bowden SJ, Kalliala I, Veroniki AA, et al. The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis. EBioMedicine. 2019;50:246-259.
Kelly H, Benavente Y, Pavon MA, De Sanjose S, Mayaud P, Lorincz AT. Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis. Br J Cancer. 2019;121:954-965.
Leeman A, Del Pino M, Marimon L, et al. Reliable identification of women with CIN3+ using hrHPV genotyping and methylation markers in a cytology-screened referral population. Int J Cancer. 2019;144:160-168.
van Leeuwen RW, Oštrbenk A, Poljak M, van der Zee AGJ, Schuuring E, Wisman GBA. DNA methylation markers as a triage test for identification of cervical lesions in a high risk human papillomavirus positive screening cohort. Int J Cancer. 2019;144:746-754.
Clarke MA, Gradissimo A, Schiffman M, et al. Human papillomavirus DNA methylation as a biomarker for cervical precancer: consistency across 12 genotypes and potential impact on management of HPV-positive women. Clin Cancer Res. 2018;24:2194-2202.
Luttmer R, De Strooper LM, Berkhof J, et al. Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study). Int J Cancer. 2016;138:992-1002.
Lazcano-Ponce EC, Alonso de Ruiz P, Lopez-Carrillo L, et al. Validity and reproducibility of cytologic diagnosis in a sample of cervical cancer screening centers in Mexico. Acta Cytol. 1997;41:277-284.
Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132:810-819.
Ferreccio C, Bratti MC, Sherman ME, et al. A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:815-823.
Murillo R, Wiesner C, Cendales R, Piñeros M, Tovar S. Comprehensive evaluation of cervical cancer screening programs: the case of Colombia. Salud Publica Mex. 2011;53:469-477.
Wagner S, Roberson D, Boland J, et al. Evaluation of TypeSeq, a novel high-throughput, low-cost, next-generation sequencing-based assay for detection of 51 human papillomavirus genotypes. J Infect Dis. 2019;220:1609-1619.