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Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

ABSTRACT: As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

SUBMITTER: Suiter CC

PROVIDER: S-EPMC7071893 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

Suiter Chase C CC Moriyama Takaya T Matreyek Kenneth A KA Yang Wentao W Scaletti Emma Rose ER Nishii Rina R Yang Wenjian W Hoshitsuki Keito K Singh Minu M Trehan Amita A Parish Chris C Smith Colton C Li Lie L Bhojwani Deepa D Yuen Liz Y P LYP Li Chi-Kong CK Li Chak-Ho CH Yang Yung-Li YL Walker Gareth J GJ Goodhand James R JR Kennedy Nicholas A NA Klussmann Federico Antillon FA Bhatia Smita S Relling Mary V MV Kato Motohiro M Hori Hiroki H Bhatia Prateek P Ahmad Tariq T Yeoh Allen E J AEJ Stenmark Pål P Fowler Douglas M DM Yang Jun J JJ

Proceedings of the National Academy of Sciences of the United States of America 20200224 10

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function as ...[more]

PMID: 32094176

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Project description:BackgroundNUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure.MethodsWhole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on well-known NUDT15 and TPMT were evaluated by multigene prediction models.ResultsAmong the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913).ConclusionsThe CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Dataset Information

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

Publications

Massively parallel variant characterization identifies <i>NUDT15</i> alleles associated with thiopurine toxicity.

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