A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma.
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
06 Dec 2023
06 Dec 2023
Historique:
received:
28
02
2023
revised:
09
06
2023
accepted:
04
07
2023
pmc-release:
19
07
2024
medline:
11
12
2023
pubmed:
19
7
2023
entrez:
19
7
2023
Statut:
ppublish
Résumé
The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening. We measured methylation levels at CpG sites in the L2/L1 open reading frames of HPV16, HPV18, and HPV45-as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with AIS/ADC, 2) 353 with cervical intraepithelial neoplasia-3 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n = 579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n = 292). CpG site-specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested. Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS/ADC, and as well as those with CIN3/SCC, relative to either control group (weakest P = .004). The Methylation Score for AIS/ADC had a sensitivity of 74% and specificity of 89%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS/ADC was ORq4-q1 = 49.01 (PBenjamini-Hochberg = 4.64E-12), using HPV-Clearers as controls. CIN3/SCC had similar, albeit weaker, associations with the Methylation Score. HPV16/18/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).
Sections du résumé
BACKGROUND
BACKGROUND
The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening.
METHODS
METHODS
We measured methylation levels at CpG sites in the L2/L1 open reading frames of HPV16, HPV18, and HPV45-as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with AIS/ADC, 2) 353 with cervical intraepithelial neoplasia-3 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n = 579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n = 292). CpG site-specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested.
RESULTS
RESULTS
Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS/ADC, and as well as those with CIN3/SCC, relative to either control group (weakest P = .004). The Methylation Score for AIS/ADC had a sensitivity of 74% and specificity of 89%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS/ADC was ORq4-q1 = 49.01 (PBenjamini-Hochberg = 4.64E-12), using HPV-Clearers as controls. CIN3/SCC had similar, albeit weaker, associations with the Methylation Score.
CONCLUSIONS
CONCLUSIONS
HPV16/18/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).
Identifiants
pubmed: 37467068
pii: 7226515
doi: 10.1093/jnci/djad134
pmc: PMC10699843
doi:
Substances chimiques
DNA, Viral
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1535-1543Subventions
Organisme : NCI NIH HHS
ID : U01 CA078527
Pays : United States
Organisme : NCI NIH HHS
ID : 5U01CA078527
Pays : United States
Organisme : NIH HHS
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Références
Am J Clin Pathol. 2019 Mar 1;151(4):433-442
pubmed: 30649177
J Natl Cancer Inst. 2018 May 1;110(5):501-508
pubmed: 29145648
PLoS One. 2016 Nov 3;11(11):e0163793
pubmed: 27812088
Cancer. 2004 Mar 1;100(5):1035-44
pubmed: 14983500
Clin Infect Dis. 2022 Mar 9;74(5):814-820
pubmed: 34143885
Gynecol Oncol. 2015 Feb;136(2):178-82
pubmed: 25579107
Expert Rev Mol Diagn. 2017 Apr;17(4):379-391
pubmed: 28277144
Cancer Epidemiol Biomarkers Prev. 2018 Dec;27(12):1407-1415
pubmed: 30237251
Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):159-69
pubmed: 20056635
Clin Infect Dis. 2021 May 4;72(9):1529-1537
pubmed: 32881999
JAMA. 2018 Aug 21;320(7):674-686
pubmed: 30140884
Cancer. 2005 Mar 15;103(6):1258-64
pubmed: 15693030
Int J Cancer. 2017 Aug 15;141(4):701-710
pubmed: 28500655
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Obstet Gynecol. 2020 Apr;135(4):869-878
pubmed: 32168211
CA Cancer J Clin. 2021 May;71(3):209-249
pubmed: 33538338
J Natl Cancer Inst. 2012 Nov 21;104(22):1738-49
pubmed: 23093560
Lancet. 2003 Jan 4;361(9351):40-3
pubmed: 12517465
Gynecol Oncol. 2015 Jul;138(1):94-100
pubmed: 26001326
Cancer Epidemiol Biomarkers Prev. 2011 May;20(5):946-53
pubmed: 21415357
Int J Cancer. 2015 Feb 15;136(4):E146-53
pubmed: 25081507
CA Cancer J Clin. 2020 Sep;70(5):321-346
pubmed: 32729638
Bioinformatics. 2011 Jun 1;27(11):1571-2
pubmed: 21493656
Histopathology. 2020 Jan;76(1):112-127
pubmed: 31846527
Clin Cancer Res. 2018 May 1;24(9):2194-2202
pubmed: 29420222
BMC Cancer. 2007 Aug 23;7:164
pubmed: 17718897