Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma

Abstract

BackgroundDespite advances in combined modality therapy, outcomes in head and neck squamous cell cancer (HNSCC) remain dismal with five-year overall survival rates of less than 50%. Prognostic biomarkers are urgently needed to identify patients with a high risk of death after initial curative treatment. Methylation status of the paired-like homeodomain transcription factor 2 (PITX2) has recently emerged as a powerful prognostic biomarker in various cancers. In the present study, the clinical performance of PITX2 methylation was validated in a HNSCC cohort by means of an independent analytical platform (Infinium HumanMethylation450 BeadChip, Illumina, Inc.).MethodsA total of 528 HNSCC patients from The Cancer Genome Atlas (TCGA) were included in the study. Death was defined as primary endpoint. PITX2 methylation was correlated with overall survival and clinicopathological parameters.ResultsPITX2 methylation was significantly associated with sex, tumor site, p16 status, and grade. In univariate Cox proportional hazards analysis, PITX2 hypermethylation analyzed as continuous and dichotomized variable was significantly associated with prolonged overall survival of HNSCC patients (continuous: hazard ratio (HR) = 0.19 [95%CI: 0.04–0.88], p = 0.034; dichotomized: HR = 0.52 [95%CI: 0.33–0.84], p = 0.007). In multivariate Cox analysis including established clinicopathological parameters, PITX2 promoter methylation was confirmed as prognostic factor (HR = 0.28 [95%CI: 0.09–0.84], p = 0.023).ConclusionUsing an independent analytical platform, PITX2 methylation was validated as a prognostic biomarker in HNSCC patients, identifying patients that potentially benefit from intensified surveillance and/or administration of adjuvant/neodjuvant treatment, i.e. immunotherapy.

DNA methylation biomarkers for head and neck squamous cell carcinoma

“…In addition, the methylation profile of gene promoters was different for each type of tumor [46], suggesting that the detection of aberrant gene promoter methylation could serve as a potential molecular biomarker for tumors. The evaluation of methylation profiles as a tool for the diagnosis or prognosis of tumors has been described for many cancers, such as colorectal cancer [52], nasopharyngeal carcinoma [53], laryngeal squamous cell carcinoma [54], and HNSCC [55].…”

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway

“…In breast cancer cells, upregulation of PITX2 promotes letrozole resistance via transcriptional activation of IFITM1 signaling [52]. The PITX2 DNA methylation was confirmed as a biomarker for the risk and prognosis of colorectal carcinoma [53], head and neck squamous cell carcinoma [54], urothelial bladder cancer [55] and prostate cancer [56]. Increasing researches are showing the significance of development-related genes in cancer progression.…”

Human papillomavirus elevated genetic biomarker signature by statistical algorithm

“…overexpression. There is a risk of diseases associated with PITX2 and DNA methylation in patients with non-small-cell lung cancer (Sailer et al, 2017).…”