Human papillomavirus DNA methylation as a biomarker for cervical precancer: Consistency across 12 genotypes and potential impact on management of hpv-positive women

Megan A. Clarke, Ana Gradissimo, Mark Schiffman, Jessica Lam, Christopher C. Sollecito, Barbara Fetterman, Thomas Lorey, Nancy Poitras, Tina R. Raine-Bennett, Philip E. Castle, Nicolas Wentzensen, Robert D. Burk

Research output: Contribution to journalArticle

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Abstract

Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. Experimental Design: In this nested case–control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisul-fite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives. Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women.

Original languageEnglish (US)
Pages (from-to)2194-2202
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number9
DOIs
StatePublished - May 1 2018

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DNA Methylation
Methylation
Biomarkers
Genotype
Cervical Intraepithelial Neoplasia
Triage
Cell Biology
Area Under Curve
Papillomavirus Infections
Early Detection of Cancer
Uterine Cervical Neoplasms
Research Design
Adenocarcinoma in Situ
Infection

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Human papillomavirus DNA methylation as a biomarker for cervical precancer : Consistency across 12 genotypes and potential impact on management of hpv-positive women. / Clarke, Megan A.; Gradissimo, Ana; Schiffman, Mark; Lam, Jessica; Sollecito, Christopher C.; Fetterman, Barbara; Lorey, Thomas; Poitras, Nancy; Raine-Bennett, Tina R.; Castle, Philip E.; Wentzensen, Nicolas; Burk, Robert D.

In: Clinical Cancer Research, Vol. 24, No. 9, 01.05.2018, p. 2194-2202.

Research output: Contribution to journalArticle

Clarke, MA, Gradissimo, A, Schiffman, M, Lam, J, Sollecito, CC, Fetterman, B, Lorey, T, Poitras, N, Raine-Bennett, TR, Castle, PE, Wentzensen, N & Burk, RD 2018, 'Human papillomavirus DNA methylation as a biomarker for cervical precancer: Consistency across 12 genotypes and potential impact on management of hpv-positive women', Clinical Cancer Research, vol. 24, no. 9, pp. 2194-2202. https://doi.org/10.1158/1078-0432.CCR-17-3251
Clarke, Megan A. ; Gradissimo, Ana ; Schiffman, Mark ; Lam, Jessica ; Sollecito, Christopher C. ; Fetterman, Barbara ; Lorey, Thomas ; Poitras, Nancy ; Raine-Bennett, Tina R. ; Castle, Philip E. ; Wentzensen, Nicolas ; Burk, Robert D. / Human papillomavirus DNA methylation as a biomarker for cervical precancer : Consistency across 12 genotypes and potential impact on management of hpv-positive women. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 9. pp. 2194-2202.
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abstract = "Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. Experimental Design: In this nested case–control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisul-fite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80{\%}, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80{\%} vs. 76.6{\%}) and lower test positivity compared with cytology (38.5{\%} vs. 48.7{\%}). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives. Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women.",
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T2 - Consistency across 12 genotypes and potential impact on management of hpv-positive women

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AU - Gradissimo, Ana

AU - Schiffman, Mark

AU - Lam, Jessica

AU - Sollecito, Christopher C.

AU - Fetterman, Barbara

AU - Lorey, Thomas

AU - Poitras, Nancy

AU - Raine-Bennett, Tina R.

AU - Castle, Philip E.

AU - Wentzensen, Nicolas

AU - Burk, Robert D.

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N2 - Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. Experimental Design: In this nested case–control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisul-fite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives. Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women.

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