PITX3DNA methylation is an independent predictor of overall survival in patients with head and neck squamous cell carcinoma.
Molecular biomarkers assisting risk-group assignment and subsequent treatment stratification are urgently needed for patients with squamous cell cancer of the head and neck region (HNSCC). Aberrant methylation is a frequent event in cancer and, therefore, a promising source for potential biomarkers. Here, the methylation status of the paired-like homeodomain transcription factor 3 (PITX3) was evaluated in HNSCC.



Using a quantitative real-time PCR,PITX3methylation was assessed in a cohort of 326 HNSCC patients treated for localized or locally advanced disease (training cohort). The results were validated with Infinium HumanMethylation450 BeadChip data from a 528 HNSCC patient cohort (validation cohort) generated by The Cancer Genome Atlas (TCGA) Research Network.



PITX3methylation was significantly higher methylated in tumor compared to normal adjacent tissue (NAT; training cohort: median methylation NAT 32.3%, tumor 71.8%,p< 0.001; validation cohort: median methylation NAT 16.9%, tumor 35.9%,p< 0.001).PITX3methylation was also significantly correlated with lymph node status both in the training (p= 0.006) and validation (p< 0.001) cohort.PITX3methylation was significantly higher in HPV-associated (p16-positive) tumors compared to p16-negative tumors (training cohort: 73.7 vs. 66.2%,p= 0.013; validation cohort: 40.0 vs. 33.1%,p= 0.015). Hypermethylation was significantly associated with the risk of death (training cohort: hazard ratio (HR) = 1.80, [95% confidence interval (CI) 1.20-2.69],p= 0.005; validation cohort: HR = 1.43, [95% CI 1.05-1.95],p= 0.022). In multivariate Cox analyses,PITX3added independent prognostic information. Messenger RNA (mRNA) expression analysis revealed an inverse correlation withPITX3methylation in the TCGA cohort.



PITX3DNA methylation is an independent prognostic biomarker for overall survival in patients with HNSCC and might aid in the process of risk stratification for individualized treatment.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY USA.|Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY USA.
Verena
V
Sailer
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Emily Eva
EE
Holmes
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Heidrun
H
Gevensleben
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
Diane
D
Goltz
Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Freya
F
Dröge
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Alina
A
Franzen
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Jörn
J
Dietrich
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Glen
G
Kristiansen
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Friedrich
F
Bootz
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Andreas
A
Schröck
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Dimo
D
Dietrich
D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000821:virology; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000235:genetics*; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3
Biomarker; DNA methylation; HNSCC; HPV; Head and neck squamous cell carcinoma; PITX3; Prognosis