PII-077 - EVALUATING THE ACCURACY OF PHARMACOGENOTYPE EXTRACTION FROM SOMATIC WHOLE EXOME SEQUENCING

W. Osei¹, T. Shugg², R. Ly³, S. Bray⁴, B. SALISBURY⁵, R. Ratcliff⁴, V. PRATT⁶, I. NUMANAGIC⁷, T. Skaar²; ¹Purdue University College of Pharmacy, , Indiana University School of Medicine, ²Indiana University School of Medicine, Division of Clinical Pharmacology, ³Indiana University School of Medicine, ⁴LifeOmic, ⁵PATIENT NETWORK & DATA, ⁶AGENA BIOSCIENCE, ⁷UNIVERSITY OF VICTORIA.

Background: Pharmacogenomics (PGx) testing can help reduce toxicities and improve efficacy of several drugs used to treat cancer and associated symptoms. PGx results can be determined from germline whole-exome sequencing (WES), but somatic mutations may cause discordance between tumor and germline DNA. Since clinical diagnostic sequencing in oncology frequently only includes tumor DNA, there would be clinical value in calling germline PGx genotypes from tumor DNA. Thus, the goal of this study was to assess the feasibility of using somatic WES data to call germline PGx genotypes.

Methods: Germline and somatic WES data were obtained as part of the clinical workflow for 719 patients treated at the Indiana University Precision Genomics Clinic. Aldy v3.3 was implemented using the default settings in LifeOmic’s Precision Health Cloud™ to call PGx genotypes from somatic WES. Somatic Aldy calls were compared with previously validated Aldy germline calls for 13 genes: CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, G6PD, NUDT15, SLCO1B1 and TPMT. Somatic read depth was >100x, except for the intronic CYP3A4*22 variant, which was >30x.

Results: Somatic and germline Aldy calls were compared. Based on 9347 genotypes, 781 (8%) calls were discordant. Discordant calls were most common in CYP2B6 (26%) and CYP2D6 (24%), followed by SLCO1B1 (23%), DPYD (10%), and CYP2C19 (9%). In contrast, all Aldy calls for G6PD and NUDT15 were concordant. Discordant calls for at least one variant were observed in 449 (62%) of the 719 individuals. Colorectal (12%), breast (12%), prostate (6%), and non-small cell lung (6%), were the most common first cancer diagnoses in our group, and the frequencies of discordant Aldy calls did not appear to differ by cancer type (p>0.05).

Conclusion: Pharmacogenetic genotyping from somatic tumor DNA may be useful as a screening tool; however, additional work needs to be done to determine if the remaining discordant calls can be corrected by modifying the informatics tools or if they are due to somatic mutations.