New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development.
DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPL) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were nonmethylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A methylation index was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high methylation index had a worse oral cancer-free survival (P = 0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse oral cancer-free survival (P = 0.0153). In conclusion, AGTR1, FOXI2, and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs.
Cancer Research Center of Lyon, UMR INSERM 1052-CNRS 5286, Lyon, France. Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France. Department of Oral and Maxillo-Facial Surgery, Hôpital Pitié Salpêtrière, Paris, France.
Jean-Philippe
JP
Foy
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Curtis R
CR
Pickering
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Vassiliki A
VA
Papadimitrakopoulou
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
Jaroslav
J
Jelinek
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Steven H
SH
Lin
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
William N
WN
William
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mitchell J
MJ
Frederick
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jing
J
Wang
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wenhua
W
Lang
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lei
L
Feng
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Li
L
Zhang
Levine Cancer Institute, Carolinas Health Care System, Charlotte, North Carolina.
Edward S
ES
Kim
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
You H
YH
Fan
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Waun K
WK
Hong
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Adel K
AK
El-Naggar
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
J Jack
JJ
Lee
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jeffrey N
JN
Myers
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
Jean-Pierre
JP
Issa
UC San Diego Moores Cancer Center, San Diego, California. pierre.saintigny@lyon.unicancer.fr LMao@umaryland.edu slippman@ucsd.edu.
Scott M
SM
Lippman
Oncology and Diagnostic Science, University of Maryland Dental School, Baltimore, Maryland. pierre.saintigny@lyon.unicancer.fr LMao@umaryland.edu slippman@ucsd.edu.
Li
L
Mao
Cancer Research Center of Lyon, UMR INSERM 1052-CNRS 5286, Lyon, France. Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France. Department of Medicine, Centre Léon Bérard, Lyon, France. Université de Lyon, Lyon, France. pierre.saintigny@lyon.unicancer.fr LMao@umaryland.edu slippman@ucsd.edu.
Pierre
P
Saintigny
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D017422:Sequence Analysis, DNA
C544065:AGTR1 protein, human; D044140:Receptor, Angiotensin, Type 1