Abstract B66: Contribution of mitochondrial ancestry in cancer health disparities

Abstract

Abstract Mitochondria are maternally inherited. The mitochondrial genome along with mitochondria is also inherited only through the mother. The mitochondrial genome serves as a determinant of ethnicity. Indeed, the mitochondrial genome sequence of African Americans (AAs) differs from Caucasian Americans (CAs). The mitochondrial genome encodes 22tRNAs, two rRNAs, and 13 polypeptides of respiratory enzyme complexes and oxidative phosphorylation. To date, it is not known if ethnic differences in mitochondrial genetic ancestry affect mitochondrial function and contribute to cancer disparities. The goal of our laboratory is to identify the nuclear and mitochondrial genetic determinants of mitochondrial function that contribute to cancer disparities in racially different populations. Mitochondria are multifunctional organelles and are implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Unlike nuclear DNA, the copy number of mtDNA (mtDNA content) varies in different tissues. We previously have demonstrated that, in addition to the sequence, there is a difference in mtDNA content between the prostate tissues of AAs and CAs. We showed that 1) normal prostates of AAs harbor reduced mtDNA content compared to those for CAs and 2), when adjusted for age, Gleason grade, and prostate-specific antigen (PSA), the prostate tumors of AAs contained more than six-fold less mtDNA than tumors of CAs. To identify the basis for the quantitative differences in mtDNA content in different races, we conducted comprehensive bioinformatics analyses of variants for more than 5,000 AAs and 33,000 CAs. We focused on POLG1 (mtDNA polymerase g), the only replicative DNA polymerase known to function in human mitochondria. We have identified missense variants in exonuclease and polymerase domain of POLG1. We found amino acid 1143 (E1143G) to be 25 times more prevalent in CA when compared to AA population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in CA. Expression of these variants increased glucose consumption, decreased ATP production, and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible, suggesting a role of epigenetic regulators. Our recent studies identified distinctive POLG1 variant exclusively present in AAs. We will show data on how distinctive AAs variants impact mitochondrial genetics and mitochondrial function, which may contribute to prostate cancer disparity in men of African ancestry. In ethnic populations, differences in mitochondrial function may alter the crosstalk between mitochondria and the nucleus at epigenetic and genetic levels, which may underlie cancer health disparities. Targeting race-specific distinctive mitochondrial determinants may provide a promising strategy for the development of selective anticancer therapy for reducing cancer health disparities. Note: This abstract was not presented at the conference. Citation Format: Bajpai Prachi, Bhupendra Singh, Keshav Singh. Contribution of mitochondrial ancestry in cancer health disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B66.