Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

Abstract

With an estimated global population of cancer survivors exceeding 32 million and growing, there is a heightened awareness of the long-term toxicities resulting from cancer treatments and their impact on quality of life. Unexplained heterogeneity in the persistence and development of toxicities, as well as an incomplete understanding of their mechanisms have generated a growing need for the identification of predictive pharmacogenomic markers. Early studies addressing this need used a candidate gene approach; however, over the last decade, unbiased and comprehensive genome-wide association studies (GWAS) have provided markers of phenotypic risk and potential targets to explore the mechanistic and regulatory pathways of biological functions associated with chemotherapeutic toxicity. In this review, we provide the current status of GWAS of chemotherapeutic toxicities with an emphasis on examining the ancestral diversity of the representative cohorts within these studies. Persistent calls to incorporate both ancestrally diverse and/or admixed populations into genomic efforts resulted in a recent rise in the number of studies utilizing cohorts of East Asian descent; however, few pharmacogenomic studies to date include cohorts of African, Indigenous American, Southwest Asian, and admixed populations. Through comprehensively evaluating sample size, composition by ancestry, genome-wide significant variants, and population-specific minor allele frequencies as reported by HapMap/dbSNP using NCBI PubMed, and the NHGRI-EBI GWAS Catalog, we illustrate allele frequencies and effect sizes tend to vary among individuals of differing ancestries. In an era of Personalized Medicine, the lack of diversity in genome-wide studies of anticancer agent toxicity may contribute to the health disparity gap.

Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities

“…In addition to the disproportionate number of studies that have used candidate gene approaches to probe cisplatin-induced toxicities, few investigations have evaluated these adverse sequelae in cohorts not predominantly/exclusively of European ancestry. This observation mirrors the lack of ancestral diversity represented in GWAS of chemotherapeutic toxicities despite known differences in allele frequencies and effect sizes among individuals of differing ancestries (82). One reason for this is that several GWAS were performed in testicular cancer survivors, a disease that disproportionately affects white males (83).…”

Genetic Predisposition to Neuroblastoma

“…This suggests that different ethnic and racial groups are likely to have unique predisposing genetic factors [ 123 , 124 ]. Furthermore, deficiencies of understanding the differences in genetic predispositions between ethnicities can lead to unsuccessful applications of genomics in the clinic [ 125 , 126 ]. While some studies in neuroblastoma have used an African American cohort to validate findings from Caucasians [ 99 , 101 , 127 ], primary genome-wide analyses of race and ethnicities other than Caucasians have been sparse.…”

Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment

“…Notably, both variants identified through GWAS are extremely rare in the East Asian population (0.011 for rs1872328 in ACYP2 and 0.003 for rs62283056 in WFS1) pointing to the importance of inclusion of diverse cohorts in future pharmacogenomics studies to ensure that the benefits of genomic medicine are realized for all. 103…”