Concordance of somatic whole exome sequencing and germline genotyping of DPYD to screen for DPD deficiency.

Abstract

10584 Background: Fluoropyrimidines are amongst the most commonly used chemotherapeutic agents in the treatment of gastrointestinal and breast malignancies. Fluoropyrimidines carry a risk of severe adverse events in the 2-3 % of the population with DPD deficiency caused by decreased function variants of DPYD. As a result, pre-treatment testing to identify patients with decreased function variants including DPYD genotyping is critical. However, pre-treatment DPYD genotyping is not yet broadly used in the United States. We hypothesized that our in-house somatic exome DHCancerSeq assay could serve as an effective tool to screen for DPD deficiency. Methods: We identified patients in our health system with somatic whole exome sequencing who had clinical DPYD genotyping using either a limited real time PCR assay (including the *2A, *13, and c.2846A > T alleles) or a dedicated NGS-based PGx panel covering all known clinically relevant mutations in DPYD. HapB3 screening on the somatic whole exome was performed using only the coding sequence variant (c.1236G > A), not the causative deep intronic variant (c.1129-5923C > G), given the known high linkage disequilibrium amongst these variants. We then evaluated concordance of somatic whole exome sequencing and targeted germline genotyping. Results: A total of 115 patients had DPYD genotyping results from both somatic and germline testing and were eligible for evaluation of concordance (48 germline PCR tests and 67 NGS based). There was complete (100%) concordance of genotypes across germline and somatic assays, with genotypes of DPYD *1/*1 (106/106 samples), *1/*2A (3/3), *1/*13 (2/2) and *1/HapB3 (4/4). Conclusions: There was 100% concordance of somatic whole exome sequencing with traditional germline testing for DPYD deficiency. While germline testing remains the standard of care given the nuances of somatic copy number changes, our results suggest that somatic whole exome sequencing is a viable and efficient screening tool for DPD deficiency.