Detection of hypermethylated genes as markers for cervical screening in women living with HIV

J Int AIDS Soc. 2018 Aug;21(8):e25165. doi: 10.1002/jia2.25165.

Abstract

Introduction: To evaluate the performance of hypermethylation analysis of ASCL1, LHX8 and ST6GALNAC5 in physician-taken cervical scrapes for detection of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 in women living with HIV (WLHIV) in South Africa.

Methods: Samples from a prospective observational cohort study were used for these analyses. Two cohorts were included: a cohort of WLHIV who were invited for cervical screening (n = 321) and a gynaecologic outpatient cohort of women referred for evaluation of abnormal cytology or biopsy proven cervical cancer (n = 108, 60% HIV seropositive). Cervical scrapes collected from all subjects were analysed for hypermethylation of ASCL1, LHX8 and ST6GALNAC5 by multiplex quantitative methylation specific PCR (qMSP). Histology endpoints were available for all study subjects.

Results: Hypermethylation levels of ASCL1, LHX8 and ST6GALNAC5 increased with severity of cervical disease. The performance for detection of CIN3 or worse (CIN3+ ) as assessed by the area under the receiver operating characteristic (ROC) curves (AUC) was good for ASCL1 and LHX8 (AUC 0.79 and 0.81 respectively), and moderate for ST6GALNAC5 (AUC 0.71). At a threshold corresponding to 75% specificity, CIN3+ sensitivity was 72.1% for ASCL1 and 73.8% for LHX8 and all samples from women with cervical cancer scored positive for these two markers.

Conclusions: Hypermethylation analysis of ASCL1 or LHX8 in cervical scrape material of WLHIV detects all cervical carcinomas with an acceptable sensitivity and good specificity for CIN3+ , warranting further exploration of these methylation markers as a stand-alone test for cervical screening in low-resource settings.

Keywords: DNA Methylation Marker Testing; Early Detection of Cancer; High-grade Cervical Intraepithelial Neoplasia; Human Immuno-deficiency Virus; Human Papillomavirus; Uterine Cervical Neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor
  • Cervical Intraepithelial Neoplasia / complications
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • Cervical Intraepithelial Neoplasia / genetics
  • Coenzyme A Ligases / genetics
  • Cohort Studies
  • DNA Methylation*
  • DNA, Neoplasm / metabolism*
  • Early Detection of Cancer
  • Female
  • HIV Infections / complications
  • HIV Infections / genetics*
  • Humans
  • LIM-Homeodomain Proteins / genetics
  • Mass Screening
  • Middle Aged
  • Prospective Studies
  • ROC Curve
  • Sialyltransferases / genetics
  • South Africa
  • Transcription Factors / genetics
  • Uterine Cervical Neoplasms / complications
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / genetics

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • LIM homeobox protein 8
  • LIM-Homeodomain Proteins
  • Transcription Factors
  • Sialyltransferases
  • brain-specific GD1alpha synthase, ST6GalNAc V
  • Coenzyme A Ligases
  • ACSL1 protein, human