TY - JOUR
T1 - New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development
AU - Foy, Jean Philippe
AU - Pickering, Curtis R.
AU - Papadimitrakopoulou, Vassiliki A.
AU - Jelinek, Jaroslav
AU - Lin, Steven H.
AU - William, William N.
AU - Frederick, Mitchell J.
AU - Wang, Jing
AU - Lang, Wenhua
AU - Feng, Lei
AU - Zhang, Li
AU - Kim, Edward S.
AU - Fan, You H.
AU - Hong, Waun K.
AU - El-Naggar, Adel K.
AU - Lee, J. Jack
AU - Myers, Jeffrey N.
AU - Issa, Jean Pierre
AU - Lippman, Scott M.
AU - Mao, Li
AU - Saintigny, Pierre
N1 - Publisher Copyright:
© 2015 AACR.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
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U2 - 10.1158/1940-6207.CAPR-14-0179
DO - 10.1158/1940-6207.CAPR-14-0179
M3 - Article
C2 - 26342026
AN - SCOPUS:84946117437
SN - 1940-6207
VL - 8
SP - 1027
EP - 1035
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 11
ER -