Inferring germline pharmacogenomics from tumor transcriptome.

Objectives: Pharmacogenomic testing is rapidly becoming the standard of care in treating pediatric acute lymphoblastic leukemia (ALL). Risk classification of ALL can be performed through whole transcriptome sequencing (WTS) of diagnostic tumor samples. We evaluated the feasibility of inferring germline pharmacogenomic genotypes from the tumor transcriptome in ALL.

Methods: Transcriptome and paired tumor-germline genome sequencing data were collected from clinical testing at St. Jude Children's Research Hospital. Genotypes for pharmacogenes that are actionable for medications used in the management of pediatric ALL (TPMT, NUDT15, and G6PD) were determined using a rule-based algorithm from transcriptome data. WTS-derived genotype calls were compared with germline genotypes obtained from whole genome sequencing (WGS) and clinical genotyping assays.

Results: Among 650 patients with ALL, 36 (5.5%) patients had somatic copy number loss on chromosomes 6, 13, or X, where TPMT, NUDT15, and G6PD are located, respectively. For the remaining 614 patients, WTS provided thiopurine dosing guidance by calling both TPMT and NUDT15 diplotypes in 545 patients (83.8%). For G6PD, accurate genotyping was called for 367 male patients. We observed a greater than 99% concordance between tumor WTS and germline WGS diplotypes for all three genes.

Conclusion: The leukemia transcriptome can be used to provide accurate genotyping calls for select germline pharmacogenes actionable in the treatment of pediatric ALL.