Prevalence of genetic polymorphisms associated with anti-cancer drug efficacy and toxicity in the South African population

Abstract

Cancer is a leading cause of morbidity and mortality in both industrialized and developing nations. The true incidence of cancer in unknown in many developing countries, where the burden of the human immunodeficiency virus and tuberculosis take priority. Lung cancer and female breast cancer have the highest number of new cases globally, followed by colorectal cancer, prostate cancer, and stomach cancer. Treatment failure is not uncommon in these types of cancer and are often life threatening. To improve treatment outcome, focus has shifted to incorporate precision medicine. This involves pharmacogenomics which aims to understand how genetic variations influence drug efficacy and toxicity, and how these individual genetic variations affect the manner in which an individual will respond to a specific drug regime or dosage. There are some population groups for which there is limited genetic variation data sets available, such as sub-Saharan African populations. The aim of the study was to establish the prevalence of several single nucleotide polymorphisms (SNPs) that have been highlighted to not only affect the efficacy and toxicity of anti cancer drugs (but other drugs as well) within the South African population of Bantu speakers, bridging a gap in knowledge which could contribute towards improved treatment strategies for cancer treatment. The study protocol was approved by the Ethics Committee of the Faculty of Health Sciences of the University of Pretoria under protocol number 3/2020. A total of 764 DNA samples from four previously recruited cohorts of self-identified black South African Bantu speakers were assessed. The four cohorts included blood bank donors for the study of gene polymorphisms in the general population (Ethics protocol # 73/2006), women with breast cancer for the study of breast cancer genes (Ethics protocol #KCT265), men with prostate cancer for the study of prostate cancer genes (43/2010), and lastly male Tshivenda individuals who were previously enrolled as controls in a study investigating epigenomic changes due to pesticide exposure in a malaria area (Ethics protocol # 43/2003). Sixty genetic polymorphisms, consisting of a single target gene, 13 transport genes and 46 metabolisms genes were investigated. SNPs comprised of missense variants (60%), intron variants (13.3%) and synonymous variants (8.3%). The TaqMan® OpenArray™ genotyping platform was used to genotype the study cohort. The OpenArray™ platform was validated using whole iii genome sequencing. Genotype and allele frequencies for the study population were calculated and compared to data extracted from the 1000 Genomes Project on populations of African and European ancestry to determine the presence of interpopulation variation. Statistical significance (P < 0.05) was determined using both the Chi-square and Fisher exact test. Principle component analysis (PCA) was performed to visualise the variation both between the populations and within the study population. Six polymorphisms showed 100% amplification across all the samples analysed; rs1272155 (CYP2B6), rs11572103 (CYP2C8), rs35599367 (CYP3A4), rs55886062 (DPYD), rs714368 (SLC22A16) and rs1902023 (UGT2B15). The CYP2D6 locus (rs1065852, rs3892097, rs35742686 and rs28371706) had the highest no amplification call rate of all the SNPs investigated. Five variants were fixed within the population, with only homozygotes for the ancestral allele being detected in the study population namely, rs2032582 - C (ABCB1), rs12721655 - A (CYP2B6), rs7900194 – G (CYP2C9), rs55886062 - A and rs67376798 - T (DPYD). Six polymorphisms, rs1065852, rs3892097, rs35742686 and rs28371706 from CYP2D6 family, rs11615 (ERCC1) and rs1042028 (SULT1A1) were found to deviate from HWE (P < 0.05), likely because of the non-specificity of the probes rather than population stratification. The PCA analysis confirmed the presence of both inter- and intra-population diversity, highlighting the importance and need for more large-scale population-based studies of understudied populations. The mechanism of action of the drug and the role that the gene or subsequent enzyme plays in the metabolism of the drug, is the determinant of the risk variant. From the study several of the SNPs were highlighted as important polymorphisms for screening purposes prior to therapy initiation, which is in agreement with previous literature; CBR3 (rs1056892), CYP19A1 (rs4646), CYP2B6*16 (rs28399499), CYP2B6*6 (rs3745274), CYP2C19*17 (rs12248560), CYP2C19*27 (rs7902257), CYP2C8*2 (rs11572103), CYP2D6*17 (rs2837170), CYP3A4*1 (rs4986907), CYP3A4*1B (rs2740574), CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343), DPYD (rs115232898), SLCO1B3 (rs4149117 and rs7311358), UGT1A6 (rs17863783) and XRCC1 (rs25487). iv Future research should include genomic capacity development in the African continent. Policy developers need to enforce pharmacovigilance reporting, which will enable large pharmaceutical companies to assist in research and funding of projects that will investigate the underlying cause of adverse drug reactions in specific population groups within Africa.