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Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; James Solomon, MD, PhD, resident, Department of Pathology, UCSD; Richard Wong, MD, PhD, molecular pathology fellow, Department of Pathology, UCSD; and Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering Cancer Center, New York.

Variants in NUDT15: association with thiopurine–induced myelosuppression

April 2019—The thiopurines mercaptopurine, thioguanine, and azathioprine are purine antimetabolites widely used as anticancer and immunosuppressive agents. Commonly prescribed in patients with inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, they are valuable steroid-sparing treatment options. Unfortunately, approximately 15 percent of IBD patients develop adverse drug reactions, such as thiopurine-induced myelosuppression (TIM), that necessitate drug withdrawal. TIM has a cumulative incidence of seven percent in IBD patients and an estimated mortality of one percent. A similar phenomenon is also described when this class of drug is used in antineoplastic protocols. The enzyme thiopurine methyltransferase (TPMT) metabolizes thiopurines, reducing their conversion to active drug. Genetic variation in the TPMT gene can result in decreased enzyme activity, increased active drug concentrations, and subsequent bone marrow suppression. TPMT variants are found in 25 percent of patients of European ancestry affected by TIM, suggesting the presence of other genetic and environmental determinants. Studies in patients of East Asian ancestry and other populations have identified variants in nudix hydrolase 15 (NUDT15) as risk factors for TIM. The authors of this study used genome-wide association studies (GWAS) and whole exome sequencing on a large case control cohort of patients to identify genetic variants associated with TIM in a population of European ancestry. Recruiting from 89 international sites during a four-year period, they tested 311 TIM-affected and 608 unaffected IBD patients using GWAS and 328 affected and 633 unaffected patients using whole exome sequencing. When comparing patients affected with TIM and those who were unaffected, the authors found no significant differences in gender, type of IBD, behavior of IBD, or extent of disease. Affected patients were noted to be younger at the time of IBD diagnosis and received a higher weight-adjusted thiopurine dose than unaffected patients. GWAS analysis confirmed the prior reported association of TIM with TPMT (variant rs11969064), seen in 30.5 percent (95 of 311) of affected patients compared with 16.4 percent (100 of 608) of unaffected patients in this study. No other genetic associations with TIM exceeded the a priori threshold for statistical significance. Exome sequencing to investigate the role of rare coding variants revealed a TIM association with a 6–base pair in-frame deletion in exon 1 of NUDT15 (p.Gly17_Val18del) for 5.8 percent (19 of 328) of the affected patients compared with 0.2 percent (one of 633) of the unaffected patients. Variants in NUDT15 or TPMT, or both in some patients, were enriched in patients affected with early-onset TIM, which occurs no more than eight weeks after starting the maximum thiopurine dose. The only other variant outside of NUDT15 that was significantly associated with TIM in the exome sequencing data was within TPMT. Correlating functional assays with genetic data, TPMT enzyme activity levels were available for 75 percent of patients with exome analysis. All (10 of 10) patients with no TPMT activity and 73 percent of patients (80 of 109) with low TPMT activity carried various variant TPMT haplotypes. Overall, 4.9 percent (16 of 328) of affected patients and 0.2 percent (one of 633) of unaffected patients had two TIM-associated TPMT variant haplotypes. The median time to TIM was shorter for affected patients who carried NUDT15 and double TPMT variants than for affected patients who did not carry risk variants. With the ubiquitous use of thiopurines across multiple diseases, the authors’ findings are likely to have significance beyond IBD patients. According to population studies, variant NUDT15 haplotypes can be found in 29.2 percent of East Asian, 20.7 percent of Latin American, and 13.4 percent of South Asian ancestry populations. In line with these findings, recent recommendations by the Clinical Pharmacogenetics Implementation Consortium advocate for pretreatment TMPT and NUDT15 genotyping in patients slated to start thiopurine drugs.

Walker GJ, Harrison JW, Heap GA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA. 2019;321(8):773–785.

Correspondence: Dr. Tariq Ahmad at tariq.ahmad1@nhs.net

Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48(4):367–373.

Correspondence: Dr. Jun J. Yang at jun.yang@stjude.org

Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmocogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2018. doi:​10.1002/cpt.1304.

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