Pharmacogenomic diversity of clinically significant cancer treatment biomarkers in ancestrally diverse US population.

person Ekokobe Fonkem Medical College of Wisconsin, Milwaukee, WI info_outline Ekokobe Fonkem, Folefac Aminkeng, Chuck Hay, Mona M Al-Gizawiy, Jaimy Pettit, Jennifer M Connelly, Kathleen M Schmainda

Authors person Ekokobe Fonkem Medical College of Wisconsin, Milwaukee, WI info_outline Ekokobe Fonkem, Folefac Aminkeng, Chuck Hay, Mona M Al-Gizawiy, Jaimy Pettit, Jennifer M Connelly, Kathleen M Schmainda Organizations Medical College of Wisconsin, Milwaukee, WI Abstract Disclosures Research Funding No funding sources reported Background: Cancer Health Disparities (CHD), in the US is well documented. The is significant evidence of CHD treatment related outcomes along ancestry lines. Africans and Hispanics generally have higher rates of adverse drug reactions (ADR), and poorer survival and response rates when compared to Europeans and Asians. The causes of CHD treatment related outcomes are poorly understood but it is plausible to believe that CHD has a genetic basis, given that human genomic variations underlie both disease susceptibility and treatment outcomes. Our goal is to determine the genetic basis of CHD treatment related outcome, with a particular focus on under-represented and underserved populations. Methods: We will deploy pharmacogenomic (PGx) differentiation analyses using a comprehensive patient database and correlative banked tissue (~ 2,000 patients) from MCW, together with 3 international cohorts as comparators (Africans = 372, Asians = 1,250 and Europeans = 958) to: Interrogate clinically significant cancer treatment PGx biomarkers and characterize the variation across different populations. Assess the implications of genetic admixture on CHD treatment related outcomes. Evaluate the intersection of genetic diversity with pharmacogenomic diversity. Explore the distribution of age, gender, diagnosis, treatments, response, ADRs, survival, comorbidities, and concomitant medication. Results: Our initial results point to a significant genetic contribution to CHD treatment related outcomes. The enrichment of genetic risk factors for therapeutic failure, ADRs or poorer survival in patients of African vs European descent, explains the increased sensitivity to ADRs, poorer response rates, and decreased survival in patients of African vs European descent. We will extend this analysis to a multi-ethnic US cohort including Africans, Hispanics, Europeans, Asians, and First Nations. Conclusions: There is extensive PGx diversity within the US population, hence, coupling preemptive PGx testing with genetic testing is imperative for a truly equitable delivery of healthcare. There is a need for diversified representation of all population in cancer research to level the gaps in CHD. The identification of the genetic basis of CHD treatment related outcomes is imperative for predicting outcomes, and the implementation of preemptive PGx and precision medicine. Drugs Treatment Outcome Gene Variant Function Africans (n = 372) Europeans (n = 958) P Fluoropyrimidines TOXICITY/ADR DPYD rs1801265 coding NONSYN R29C (*9A) 0.489 0.222 4.46E-35 TOXICITY/ADR DPYD rs2297595 coding NONSYN M166V (c.496A>G) 0.197 0.102 1.32E-06 Thiopurines TOXICITY/ADR TPMT rs1800462 coding NONSYNON (*2) 0.104 0.004 2.29E-31 Cisplatin TOXICITY/ADR TPMT rs12201199 intron 0.489 0.062 4.30E-124 Anthracyclines TOXICITY/ADR UGT1A6 rs17863783 coding SYNON V209V (UGT1A6*4) 0.120 0.028 9.75E-15

Pre-clinical