Abstract 1499: Role of mutations and expression change of mitochondrial function related nuclear genes in oral gingivobuccal squamous cell carcinoma
Authors: Chattopadhyay Esita , Singh Richa , Roy Roshni , Roy Bidyut 
Published: July 2017

Abstract
Background: Mitochondria have long been suspected to have contribution in progression and sustenance of cancer. But mitochondria related nuclear genes have not been well-studied in oral cancer. The aim of this study is deciphering the impact of somatic mutations and expression deregulation of mitochondria related nuclear genes in oral gingivobuccal squamous cell carcinoma (GBSCC).
Methods: Nuclear-encoded genes which are functionally involved with mitochondria were enlisted from Mitocarta 2.0 and IMPI databases. Whole exome sequencing was performed with 12 paired cancer-normal GBSCC samples and somatic mutations in mitochondria related nuclear genes were extracted from the data. Expression deregulation of mitochondria related nuclear genes were quantified from whole transcriptome data of 12 paired cancer-normal GBSCC samples. Expression was re-validated in another set of 12 cancer-normal paired samples. 5 cancer-normal paired samples with whole transcriptome data were also used for reduced representation bisulfite sequencing (RRBS). Probable impact of non-synonymous somatic mutations were predicted using SIFT and POLYPHEN2 tools. Genes with possible damaging mutations and expression deregulation were taken for literature search and KEGG pathway analysis to understand their contribution in the function of mitochondria in GBSCC.
Result: Total 1561 mitochondria related nuclear genes were identified from two databases and included in the study. A total of 977 somatic mutations were identified in 583 such genes in 12 oral GBSCC samples. These mutations were distributed in exonic (346 mutations), intronic (288 mutations), splicing (4 mutations), UTR3’ (270 mutations) and UTR5’ (69 mutations) regions. Ten recurrently mutated genes (AK3, AK4, ATP10D, CASP8, ERBB4, MRPL10, NT5DC3, RYR3, SMURF1and TP53) were identified in at least 25% (3/12) of samples. Significant expression deregulation in 147 mitochondrial related nuclear genes was found from whole transcriptome data. Differential methylation was found in some of these 147 genes in 5 oral GBSCC samples. Thirty-seven genes were selected from 147 genes for expression re-validation by qPCR and expressions of 32 genes were re-validated in another set of 12 GBSCC samples. Somatically mutated and expression deregulated genes were different except two genes, ACADM and NNT, which were mutated and deregulated. Literature survey and KEGG pathway analysis revealed that most of the mutated or deregulated genes were functionally involved with biological pathways like mitochondrial metabolism, oxidative phosphorylation, apoptosis and molecular transport. It indicates possible disruption of these pathways in oral GBSCC.
Conclusion: Mitochondrial function related nuclear genes may have significant impact on oral GBSCC in maintenance and progression, but needs to be validated in larger set of samples.
Citation Format: Esita Chattopadhyay, Richa Singh, Roshni Roy, Bidyut Roy. Role of mutations and expression change of mitochondrial function related nuclear genes in oral gingivobuccal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1499. doi:10.1158/1538-7445.AM2017-1499