Mitochondrial DNA Variation in the D-LOOP and ND Loci identified in the Kenyan Population: Potential Implications for precision Oncology

Abstract

BackgroundPrecision oncology is dominated by studies focused on nuclear genomic alterations, leaving mitochondrial DNA (mtDNA) variation excluded from routine clinical genomic testing. However, mitochondria regulate oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) production, apoptosis, and metabolic reprogramming pathways that are central to chemotherapy response. Methods468 Complete mitochondrial genomes from Kenyan individuals representing diverse ethnic groups were analyzed. Seven variants associated with effect on cancer treatment were identified. These include; m.310T>C(D-loop), m.10398A>G (MT-ND3), m.13708G>A (MT-ND5), m.16189T>C, m.13928G>C, m9055G>A and m.16519T>C (D-loop). Allele frequencies and distribution were assessed. ResultsThe coding-region variants (m.10398A>G and m.13708G>A) occur in Complex I subunits and are associated with altered oxidative phosphorylation efficiency and ROS production. The control-region variants (m.16189T>C and m.16519T>C) influence mtDNA replication and copy number. These variants have been implicated in differential response to chemotherapeutic agents including platinum-based therapies and anthracyclines. m.13928G>C sits in the MT-CYB gene and could possibly affect mitochondrial respiratory function; this variant could influence how tumors respond to therapies that rely on apoptosis or ROS generation.m.9055G>A is a MT-ATP6 variant classified as benign in mitochondrial disease but may represent a marker of haplogroup background rather than a direct cancer driver. While m.310T>C itself does not encode a protein, its location in the regulatory D-loop influences mitochondrial function, which can affect how tumor cells respond to chemotherapies that rely on mitochondrial-mediated apoptosis or oxidative stress. ConclusionPharmacogenomic relevant mitochondrial variants are present in the Kenyan population. With the rise of cancer burden in Kenya there is a need carry out more studies to understand the impact of these variations on cancer treatment. This can inform the integration of mtDNA analysis into precision oncology strategies in African populations.