Allelic Variants of the DPYD Gene in Russian Patients with Cancer: The Results of Exome Sequencing.

DPYD

DPYD variants, the gene for dihydropyrimidine dehydrogenase, were classified by frequency, predicted functional effect, ClinVar and pharmacogenetic recommendations; exome sequencing detects rare variants that limited targeted tests do not capture.

Routine DPYD tests target a limited number of well-established variants, whereas the gene shows substantial population variability and may harbour rare, potentially functional alleles that these tests do not detect. This descriptive pharmacogenetic analysis covers a Russian cohort of 339 patients with malignant tumours treated with FLOT, FOLFOX or FOLFIRINOX, sequenced by exome (Illumina, KAPA HyperExome capture, depth of at least 100×, GRCh38, variant calling with GATK HaplotypeCaller), with allele frequencies compared with the non-Finnish European and East Asian populations of gnomAD v4.1.1. Seventeen DPYD variants were identified, with a distribution closer to the non-Finnish European population than to East Asian populations; the established reduced-function variant c.2846A>T (p.Asp949Val, rs67376798) was detected in a single heterozygous patient (allele frequency 0.15%), and the HapB3 proxy c.1236G>A (rs56038477) in 13 heterozygous patients (allele frequency 1.92%), i.e. 14 patients (4.13%) carrying one or the other. Rare variants, with a cohort allele frequency below 1%, were present in 11 patients (3.24%), among them p.Thr65Ala, p.Thr65Met, p.Asn151Asp and p.Val691Leu, regarded as potentially relevant but requiring functional validation. The authors conclude that exome analysis reveals a heterogeneous spectrum of variants, including established pharmacogenetic markers and rare variants that limited targeted panels would not capture, and that expanded sequencing could complement conventional pharmacogenetic testing.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure to retain is the yield of the two established markers: 4.13% of patients carry c.2846A>T or the HapB3 proxy c.1236G>A, with a further 3.24% carrying rare variants whose clinical relevance remains to be established. No toxicity data are reported, the functional effect of the rare variants is only predicted, and the c.1236G>A proxy is not a confirmed HapB3, which would require the intronic variant rs75017182: the study describes frequencies, not risks. From an exome perspective, the challenge is not detecting these variants, which sequencing already captures, but interpreting them: until their effect is functionally validated, the four rare missense variants do not support any dose adjustment.

Analysis by Dr Thibaut Benquey