TY - JOUR
T1 - Gene promoter-associated CpG island hypermethylation in squamous cell carcinoma of the tongue
AU - Bhat, Samatha
AU - Kabekkodu, Shama Prasada
AU - Jayaprakash, Chinchu
AU - Radhakrishnan, Raghu
AU - Ray, Satadru
AU - Satyamoorthy, Kapaettu
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - The present study was undertaken to explore and validate novel hypermethylated DNA regions in squamous cell carcinoma of the tongue (SCCT). Genome-wide methylation changes were identified by differential methylation hybridization (DMH) microarray and validated by bisulfite genome sequencing (BGS). The results were compared against datasets from The Cancer Genome Atlas head and neck squamous cell carcinoma (TCGA-HNSCC), Gene Expression Omnibus (GSE26549), and ArrayExpress (E-MTAB-1328). DMH identified 116 hypomethylated and 241 hypermethylated regions. Of the latter, 24 were localized to promoter or 5′-UTR regions. By BGS, promoter sequences of DAPK1, LRPPRC, RAB6C, and ZNF471 were significantly hypermethylated in tumors when compared with matched normal tissues (P < 0.0001). A TCGA-HNSCC dataset (516 cases of cancer and 50 normal tissue samples) further confirmed hypermethylation of DAPK1, RAB6C, and ZNF471. Sensitivity and specificity of methylation markers for a diagnosis of cancer were in the range of 70–100% in our study and from TCGA-HNSCC datasets, with an area under curve (AUC) of 0.83 and above. Kaplan-Meier survival analysis of TCGA-HNSCC expression data revealed that patients with low expressions of DAPK1, RAB6C, and ZNF471 showed poorer survival than patients with high expression (P = 0.02). Human papillomavirus (HPV) was found in 55% of cases, HPV16 being the predominant genotype. DAPK1 immunohistochemical staining was lower in SCCT than in normal buccal epithelial cells. This is the first study to report hypermethylation of LRPPRC, RAB6C, and ZNF471 in SCCT and its diagnostic and prognostic potentials in a specific head and neck squamous cell carcinoma.
AB - The present study was undertaken to explore and validate novel hypermethylated DNA regions in squamous cell carcinoma of the tongue (SCCT). Genome-wide methylation changes were identified by differential methylation hybridization (DMH) microarray and validated by bisulfite genome sequencing (BGS). The results were compared against datasets from The Cancer Genome Atlas head and neck squamous cell carcinoma (TCGA-HNSCC), Gene Expression Omnibus (GSE26549), and ArrayExpress (E-MTAB-1328). DMH identified 116 hypomethylated and 241 hypermethylated regions. Of the latter, 24 were localized to promoter or 5′-UTR regions. By BGS, promoter sequences of DAPK1, LRPPRC, RAB6C, and ZNF471 were significantly hypermethylated in tumors when compared with matched normal tissues (P < 0.0001). A TCGA-HNSCC dataset (516 cases of cancer and 50 normal tissue samples) further confirmed hypermethylation of DAPK1, RAB6C, and ZNF471. Sensitivity and specificity of methylation markers for a diagnosis of cancer were in the range of 70–100% in our study and from TCGA-HNSCC datasets, with an area under curve (AUC) of 0.83 and above. Kaplan-Meier survival analysis of TCGA-HNSCC expression data revealed that patients with low expressions of DAPK1, RAB6C, and ZNF471 showed poorer survival than patients with high expression (P = 0.02). Human papillomavirus (HPV) was found in 55% of cases, HPV16 being the predominant genotype. DAPK1 immunohistochemical staining was lower in SCCT than in normal buccal epithelial cells. This is the first study to report hypermethylation of LRPPRC, RAB6C, and ZNF471 in SCCT and its diagnostic and prognostic potentials in a specific head and neck squamous cell carcinoma.
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U2 - 10.1007/s00428-017-2094-2
DO - 10.1007/s00428-017-2094-2
M3 - Article
C2 - 28255813
AN - SCOPUS:85014093331
SN - 0945-6317
VL - 470
SP - 445
EP - 454
JO - Virchows Archiv
JF - Virchows Archiv
IS - 4
ER -