Abstract 1494: Interethnic germline variants in mitochondrial DNA polymerase (POLG1) induce mitochondrial dysfunction and confer tumorigenic properties
Authors: Bajpai Prachi , Singh Bhupendra , Owens Kjerstin M. , Srinivasasainagendra Vinodh , Tiwari Hemant K. , Singh Keshav K. 
Published: July 2017

Abstract
Purpose: Germline variants contribute to large fraction of the diversity observed among different ethnic groups and could give better insights in genetic predisposition and susceptibility from one population to another for certain disease including cancer. Decreased mitochondrial OXPHOS is one of the most common phenotypes of cancer cells. Mitochondrial DNA (mtDNA) depletion impairs OXPHOS and adaptive metabolic responses. In this context, DNA polymerase γ (POLG1) is known to function in human mitochondria and performs critical function of mtDNA replication and repair. POLG1 is the most frequent target of gene mutation and is involved in variety of mitochondrial diseases. POLG1 protein consists of exonuclease, linker and polymerase domain, each with distinct functions. Mutations in exonuclease domain leads to erroneous proofreading and is responsible for increased mutations in mtDNA whereas mutations in polymerase domain leads to erroneous replication and hence depletion in mtDNA. Germline variants in these domains of POLG1 may serve as important signature markers in association studies of individuals in a population study. Through our present study, we identified germline variants, examined copy number variation, expression and regulation of POLG1 gene in human cancers. We provide evidence that altered POLG1 expression as well as germline variations in POLG1 gene contribute to tumorigenesis.
Methods: A comprehensive race based bioinformatics analysis of POLG1 gene in European-American and African-American was conducted and several unique germline mutations were discovered. To analyze functional contribution of these unique germline mutations in tumor progression, these unique prevalent mutations in the evolutionary conserved regions of exonuclease and polymerase domains we generated by site directed mutagenesis and functional and tumorigenic analysis was performed.
Results: We observed marked differences in copy number variation of POLG1 through cBioPortal and Cosmic databases and validated the analysis in primary tumors and cancer cell lines. Our results also indicate that mtDNA copy number in cancer cell is governed by regulation of POLG1 methylation and demethylation status, suggestive of epigenetic regulation of POLG1. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans when compared to African-Americans population. Expression of this germline variant (E1143G) increased glucose consumption, decreased ATP production and increased matrigel invasion.
Discussion/ Conclusion: We demonstrate that POLG1 is epigenetically regulated and its unique germline variants contribute to disruption of mitochondrial function. Thus contributes to differences in increased predisposition to cancer in inter-ethnic population.
Note: This abstract was not presented at the meeting.
Citation Format: Prachi Bajpai, Bhupendra Singh, Kjerstin M. Owens, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Keshav K. Singh. Interethnic germline variants in mitochondrial DNA polymerase (POLG1) induce mitochondrial dysfunction and confer tumorigenic properties [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 1494. doi:10.1158/1538-7445.AM2017-1494