Hypermethylated ZNF582 and PAX1 genes in oral scrapings collected from cancer-adjacent normal oral mucosal sites are associated with aggressive progression and poor prognosis of oral cancer

Oral Oncol. 2017 Dec;75:169-177. doi: 10.1016/j.oraloncology.2017.11.013. Epub 2017 Nov 17.

Abstract

Objective: This study assessed whether hypermethylated ZNF582 and PAX1 genes in oral scrapings are correlated with the progression and prognosis of oral squamous cell carcinoma (OSCC).

Materials and methods: Methylation levels of ZNF582 and PAX1 genes in oral scrapings, collected from the cancer and adjacent normal oral mucosal sites of 80 OSCC patients before surgical cancer excision, were quantified using real-time methylation-specific PCR after bisulfite conversion.

Results: Both the mean methylation (M)-indices of ZNF582 and PAX1 genes in oral scrapings were significantly higher at the cancer sites than at the adjacent normal oral mucosal sites (both P < .001). In the oral scrapings collected from the adjacent normal oral mucosal sites, the higher M-index of methylated ZNF582 (ZNF582m) was significantly correlated with a more advanced clinical stage (P = .04). Moreover, the higher M-index of methylated PAX1 (PAX1m) was significantly related to larger tumor size (P = .046). When the 80 OSCC patients were classified based on gene methylation tests, using the oral scrapings collected from the adjacent normal oral mucosal sites, we found a significantly shorter 3-year overall survival in ZNF582m-positive, PAX1m-positive, and ZNF582m/PAX1m-positive OSCC patients than in ZNF582m-negative (P = .02), PAX1m-negative (P = .04), and ZNF582m/PAX1m-negative OSCC patients (P = .02), respectively. Multivariate Cox regression analyses identified ZNF582m and ZNF582m/PAX1m as independent unfavorable prognostic factors.

Conclusion: Hypermethylated ZNF582 and PAX1 genes in the oral scrapings collected from adjacent normal oral mucosal sites rather than cancer sites are associated with aggressive progression and poor prognosis of OSCC.

Keywords: DNA methylation biomarker; Oral squamous cell carcinoma; PAX1; ZNF582.

MeSH terms

  • DNA Methylation*
  • Disease Progression
  • Female
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Middle Aged
  • Mouth Mucosa / metabolism*
  • Mouth Mucosa / pathology
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / pathology*
  • Paired Box Transcription Factors / genetics*
  • Prognosis

Substances

  • Kruppel-Like Transcription Factors
  • Paired Box Transcription Factors
  • ZNF582 protein, human
  • PAX1 transcription factor