Abstract
BackgroundPatients with squamous cell cancer of the head and neck region (HNSCC) are at risk for disease recurrence and metastases, even after initial successful therapy. A tissue-based biomarker could be beneficial to guide treatment as well as post-treatment surveillance. Gene methylation status has been recently identified as powerful prognostic biomarker in HNSCC. We therefore evaluated the methylation status of the homeobox gene PITX1 and the adjacent long intergenic non-coding RNA (lincRNA) C5orf66-AS1 in publicly available datasets.MethodsGene methylation and expression data from 528 patients with HNSCC included in The Cancer Genome Atlas (TCGA, there obtained by using the Infinium HumanMethylation450 BeadChip Kit) were evaluated and methylation and expression levels of PITX1 and lincRNA C5orf66-AS1 was correlated with overall survival and other parameters. Thus, ten beads targeting PITX1 exon 3 and three beads targeting lincRNA C5orf66-AS1 were identified as significant candidates. The mean methylation of these beads was used for further correlation and the median was employed for dichotomization.ResultsBoth PITX1 exon 3 and lincRNA C5orf66-AS1 were significantly higher methylated in tumor tissue than in normal adjacent tissue (NAT) (PITX1 exon 3: tumor tissue 58.1%, NAT: 31.7%, p<0.001; lincRNA C5orf66-AS1: tumor tissue: 27.4%, NAT: 18.9%, p<0.001). In a univariate analysis, hypermethylation of both loci was significantly associated with the risk of death (univariate: exon 3: Hazard ratio (HR): 4.97 [1.78–16.71], p = 0.010, lincRNA C5orf66-AS1: Hazard ratio (HR): 12.23 [3.01–49.74], p<0.001). PITX1 exon 3 and lincRNA C5orf66-AS1 methylation was also significantly correlated with tumor localization, T category, human papilloma virus (HPV)-negative and p16-negative tumors and tumor grade. Kaplan-Meier analysis showed, that lincRNA C5orf66-AS1 hypomethylation was significantly associated with overall survival (p = 0.001) in the entire cohort as well in a subgroup of HPV-negative tumors (p = 0.003) and in patients with laryngeal tumors (p = 0.022).ConclusionMethylation status of PITX1 and even more so of lincRNA C5orf66-AS1 is a promising prognostic biomarker in HNSCC, in particular for HPV-negative patients. Further prospective evaluation is warranted.
Highlights
Squamous cell carcinoma of the head and neck region (HNSCC) is a common malignancy with 5-year survival rates ranging from 61% for laryngeal cancers to 63% for cancers of the oral cavity and pharynx [1]
Gene methylation and expression data from 528 patients with HNSCC included in The Cancer Genome Atlas (TCGA, there obtained by using the Infinium HumanMethylation450 BeadChip Kit) were evaluated and methylation and expression levels of PITX1 and long intergenic non-coding RNA (lincRNA) C5orf66-AS1 was correlated with overall survival and other parameters
The mean methylation of these beads was used for further correlation and the median was employed for dichotomization. Both PITX1 exon 3 and lincRNA C5orf66-AS1 were significantly higher methylated in tumor tissue than in normal adjacent tissue (NAT) (PITX1 exon 3: tumor tissue 58.1%, normal adjacent tissues (NATs): 31.7%, p
Summary
Squamous cell carcinoma of the head and neck region (HNSCC) is a common malignancy with 5-year survival rates ranging from 61% for laryngeal cancers to 63% for cancers of the oral cavity and pharynx [1]. Molecular features of an additional “atypical” HNSCC subtype, i.e. female patients with oral cavity tumors, who are HPV-negative and have no smoking history, have recently been described. These tumors exhibit a CpG island methylator phenotype (CIMP) with striking genomic stability, but are characterized by gene silencing through methylation events [6]. Gene methylation status has been recently identified as powerful prognostic biomarker in HNSCC. We evaluated the methylation status of the homeobox gene PITX1 and the adjacent long intergenic non-coding RNA (lincRNA) C5orf66-AS1 in publicly available datasets.
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