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Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer
Author(s) -
Clarke Megan A.,
Luhn Patricia,
Gage Julia C.,
Bodelon Clara,
Dunn S. Terence,
Walker Joan,
Zuna Rosemary,
Hewitt Stephen,
Killian J. Keith,
Yan Liying,
Miller Andrew,
Schiffman Mark,
Wentzensen Nicolas
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30781
Subject(s) - dna methylation , cancer , biology , methylation , cervical cancer , host (biology) , computational biology , genetics , dna , medicine , gene , gene expression
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin‐fixed, paraffin‐embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead‐based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t ‐test, and results were summarized by computing p ‐values. A total of 12 candidate genes ( ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature ( EPB41L3, MAL and miR‐124) were chosen for validation in an independent set of 167 liquid‐based cytology specimens using pyrosequencing and targeted, next‐generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from