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Gene promoter-associated CpG island hypermethylation in squamous cell carcinoma of the tongue

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Abstract

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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Acknowledgements

Support for this work by Indian Council of Medical Research (ICMR), Government of India; FIST, Department of Science and Technology (DST), Government of India; Vision Group on Science and Technology (K-FIST level II), BTFS Program, Government of Karnataka; and Manipal University are gratefully acknowledged.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India

    Samatha Bhat, Shama Prasada Kabekkodu, Chinchu Jayaprakash & Kapaettu Satyamoorthy

  2. Department of Oral Pathology, Manipal College of Dental Sciences, Manipal University, Manipal, 576104, India

    Raghu Radhakrishnan

  3. Department of Surgical Oncology, Kasturba Medical College, Manipal University, Manipal, 576104, India

    Satadru Ray

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  1. Samatha Bhat
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  6. Kapaettu Satyamoorthy
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Correspondence to Kapaettu Satyamoorthy.

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The study protocol was approved by the institutional ethics committee of Manipal University and was conducted in compliance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Samples were collected after obtaining the written consent document for participation in the study.

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Supplementary Fig. 1

Methylation and expression analysis on TCGA dataset. A) The methylation analysis was performed on 516 tumor and 50 normal samples. The frequency of hypermethylation was significantly higher for DAPK1, RAB6C and ZNF471 in tumor samples as opposed to normal samples by Fisher’s exact test. P ≤ 0.05 was considered as statistically significant. Sample with β value above 0.2 was considered as methylated. B) Methylation analysis in matched normal and tumor samples (50 samples each). C) The line graph shows methylation of individual CpG sites. Except LRPPRC, all three genes showed significant hypermethylation in specific CpG sites. D) Expression analysis of normal and tumor samples from TCGA HNSCC dataset. Both methylation and expression analysis were performed using Wanderer tool. Statistical analysis was performed by Fisher’s exact test using GraphPad Prism software. (JPEG 476 kb)

Supplementary Fig. 2

The hierarchical clustering and PCA analysis. The clustering and PCA analysis was performed using Partek Genomic suite software. Hierarchical clustering was performed by Euclidean distance and average linkage method. A) Hierarchical clustering of DAPK1, LRPPRC, RAB6C and ZNF471 in all the samples (left) and in matched normal and tumor samples (right) showing clear discrimination power of DNA methylation to distinguish between normal and tumor samples B) PCA analysis of all samples (left) and in matched samples (right) respectively. The use of matched samples for clustering increased mapping from 86.8% to 90.8%. C) Hierarchical clustering using DAPK1, RAB6C and ZNF471 in all samples (left) and matched samples (right). D) The corresponding PCA in all the samples (left) and matched samples (right). PCA analysis using three gene combinations increased PCA mapping to 100% in both matched and non-matched samples respectively. (JPEG 616 kb)

Supplementary Fig. 3

Survival analysis in patients head and neck cancer. The samples were classified into high expressing and low expressing DAPK1, LRPPRC, RAB6C and ZNF471 cases. Survival analysis was performed by SurvExpress software using TCGA-HNSCC, GSE26549 and E-MTAB-1328 datasets. Censoring samples are shown as “+” marks. Horizontal axis represents time to event. Dataset, outcome event, time scale, concordance index (CI), and p-value of the log-rank test are shown. Red and Green curves denote high- and low-expressing groups (indicated in the graphs as “high” and “low” risks) respectively. The number of individuals, the number of censored, and the CI of each group are shown in the top-right insets. A) Represents Kaplan-Meier curve for expressing groups, concordance index, and p-value of the log-rank testing equality of survival curves from TCGA-HNSCC. In G3 and T2 patients of TCGA-HNSCC had poor survival in high expressing category as opposed to low expressing category (P ≤ 0.005). B) Represents Kaplan Meier survival analysis using GSE26549 dataset. High expressing groups showed significantly lower survival as opposed to low expressing group. Additionally p63 high expression group had significantly lower survival. Moreover, in the high hypermethylated gene expressing group, those with high p63 expression had significantly poorer survival than those with low p63 expression. (JPEG 299 kb)

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Bhat, S., Kabekkodu, S.P., Jayaprakash, C. et al. Gene promoter-associated CpG island hypermethylation in squamous cell carcinoma of the tongue. Virchows Arch 470, 445–454 (2017). https://doi.org/10.1007/s00428-017-2094-2

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