Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma

Rong Wang, Robert W van Leeuwen, Aniek Boers, Harry G Klip, Tim de Meyer, Renske D M Steenbergen, Wim van Criekinge, Ate G J van der Zee, Ed Schuuring, G B A Wisman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC.

RESULTS: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10-5).

CONCLUSION: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.

Original languageEnglish
JournalOncotarget
DOIs
Publication statusPublished - 2016

Cite this

Wang, Rong ; van Leeuwen, Robert W ; Boers, Aniek ; Klip, Harry G ; Meyer, Tim de ; Steenbergen, Renske D M ; van Criekinge, Wim ; van der Zee, Ate G J ; Schuuring, Ed ; Wisman, G B A. / Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma. In: Oncotarget. 2016.
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title = "Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma",
abstract = "BACKGROUND: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC.RESULTS: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80{\%} and 92{\%} while between 94{\%} and 99{\%} of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36{\%} and 71{\%}, while between 71{\%} and 93{\%} of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88{\%} and 98{\%}. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80{\%} vs. 75{\%}, respectively, P>0.2), while specificity improved (42{\%} vs. 84{\%}, respectively, P < 10-5).CONCLUSION: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.",
author = "Rong Wang and {van Leeuwen}, {Robert W} and Aniek Boers and Klip, {Harry G} and Meyer, {Tim de} and Steenbergen, {Renske D M} and {van Criekinge}, Wim and {van der Zee}, {Ate G J} and Ed Schuuring and Wisman, {G B A}",
year = "2016",
doi = "10.18632/oncotarget.12598",
language = "English",
journal = "Oncotarget",
issn = "1949-2553",
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Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma. / Wang, Rong; van Leeuwen, Robert W; Boers, Aniek; Klip, Harry G; Meyer, Tim de; Steenbergen, Renske D M; van Criekinge, Wim; van der Zee, Ate G J; Schuuring, Ed; Wisman, G B A.

In: Oncotarget, 2016.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma

AU - Wang, Rong

AU - van Leeuwen, Robert W

AU - Boers, Aniek

AU - Klip, Harry G

AU - Meyer, Tim de

AU - Steenbergen, Renske D M

AU - van Criekinge, Wim

AU - van der Zee, Ate G J

AU - Schuuring, Ed

AU - Wisman, G B A

PY - 2016

Y1 - 2016

N2 - BACKGROUND: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC.RESULTS: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10-5).CONCLUSION: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.

AB - BACKGROUND: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC.RESULTS: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10-5).CONCLUSION: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.

U2 - 10.18632/oncotarget.12598

DO - 10.18632/oncotarget.12598

M3 - Article

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -