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 how 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. Clin Cancer Res; 23(15); 4010-9. ©2017 AACR.

Figure 1. Literature search of all current pharmacogenomic anticancer chemotherapeutic induced toxicity GWAS

Filters were designed to maximize initial results using PubMed [www.ncbi.nlm.nih.gov/pubmed] and the NHGRI-EBI GWAS Catalog [www.ebi.ac.uk/gwas/], followed by removing all candidate gene studies, studies of non-anticancer drugs, animal models, lymphoblastoid cell-line based GWAS and review articles. Numbers in blue boxes indicate initial query results; −338 indicates the studies that did not pass filtering criteria. The final result was 28 non-overlapping discovery studies with 17 studies including at least one replication set. Note: Search terms that yielded no results were excluded.

Figure 2. GWAS studies of Chemotherapeutic Toxicity

(A) Breakdown of toxicities from GWAS of anticancer agent toxicity studies. 15 of the 28 (54%) studies investigated myelosuppression and neuropathy. Associations to cardiotoxicity, hypertension, pancreatitis, and oral mucositis are all based on single European studies lending to potential population-based bias among these toxicities. Of the four toxicities represented by a single GWAS, only two of the studies investigating osteonecrosis and pancreatitis used broadly diverse panels of participants. († indicates a single cohort that was used to evaluate two separate toxicities.) (B) Breakdown of 28 studies by ancestry. Half of participants within the five multi-ancestral studies were of European descent (>49%), and more than 85% of all participants were either entirely of European descent, or entirely of East Asian descent. (C) Population based breakdown of participants in GWAS of pharmacogenomic anticancer agent toxicity with further breakdown into replication and discovery cohorts. More than half of the participants from the East Asian discovery GWAS come from a single Japanese study.