UGT1A1 pharmacogenetic (PGx) tests evaluate adverse event risk associated with the chemotherapy drugs irinotecan and belinostat by genotyping the promoter TA-repeat polymorphisms (*28, *36, and *37) and two exonic SNVs (*6 and *27). The prevalence of these variants differs significantly by race. In particular, the frequencies of *36 and *37 are 5% and 7%
in African-descent populations, respectively, whereas in other populations they are less than 0.2% (cf. gnomAD database). *37 is known to reduce UGT1A1 enzyme activity to a greater extent than *28; however, it is not included in the current FDA drug labels. Given the prevalence of UGT1A1-repeat alleles, compound heterozygotes (CH) carrying a TA-repeat variant and either
*6 or *27 are not uncommon. We analyzed racial differences in the prevalence of UGT1A1 variants and the potential for misassignment of metabolizer phenotype in the absence of phasing. Normal tissues from 14,580 de-identified cancer patients were sequenced for UGT1A1 using the Tempus xT 648-gene panel NGS test. TA repeat length was determined using a
bespoke Bayesian repeat calling algorithm. Four race and ethnicity categories — Non-Hispanic (NH) Asian, Hispanic or Latino, NH Black, and NH White — were imputed from continental genetic ancestry derived from 654 ancestry informative markers, as described previously. We identified 121 unique exonic variants and four promoter TA-repeat polymorphisms ([TA]5-8) in
UGT1A1. In silico analysis predicted 68 of the exonic variants as potentially deleterious. Notably, 17.6% of NH Black patients were carriers of either *36 or *37. Ninety-eight CH of potential clinical significance were identified. However, without phasing information, accurate assignment of UGT1A1 metabolizer phenotype in CH is challenging. This is particularly relevant in the NH
Asian population, where 6% of the population in the cohort are CH, a rate 6.4-fold higher than the overall cohort prevalence. Our research highlights racial differences in UGT1A1 allele frequencies, particularly among NH Black and NH Asian populations, which could influence test results and their interpretation in some patients. Further investigation in diverse populations is crucial to ensure equality in PGx testing related to cancer drug side effects.

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