PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity

Stocco, Gabriele; Yang, Wenjian; Crews, Kristine R.; Thierfelder, William E.; Decorti, Giuliana; Londero, Margherita; Franca, Raffaella; Rabusin, Marco; Valsecchi, Maria Grazia; Pei, Deqing; Cheng, Cheng; Paugh, Steven W.; Ramsey, Laura B.; Diouf, B; McCorkle, Joseph R.; Jones, Terreia S.; Pui, Ching Hon; Relling, Mary V.; Evans, William E.

doi:10.1093/hmg/dds302

Cited by 56 publications

(89 citation statements)

References 42 publications

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“…For example, MTHFR C677T and A1298C were reported to be associated with liver dysfunction during maintenance therapy for acute lymphoblastic leukemia in Japanese, 21 and rs2413739 in PACSIN2 was reported to be associated with gastrointestinal toxicity. 22 However, these associations were not as strong as NUDT15 with hair loss and leukopenia, and the results of PACSIN2 were controversial. 23 Pancreatitis is another critical adverse event of thiopurine treatment.…”

Section: Discussionmentioning

confidence: 99%

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

et al. 2015

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The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

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Section: Discussionmentioning

confidence: 99%

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

et al. 2015

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“…The polymorphism is associated with higher concentrations of methylated nucleotide metabolites of 6-MP in cells, as well as higher incidence of severe hepatotoxicity, even after adjustment for TPMT genotype [62][63][64][65][66]. Furthermore, a variant in the PACSIN2 gene has been found to modulate the activity of TPMT and is also independently associated with severe gastrointestinal toxicity due to 6-MP [70]. The UGT1A1*28 polymorphism, which has been associated with Gilbert's syndrome, has also been associated with hyperbilirubinemia during leukemia treatment in one study [30].…”

Section: Gastrointestinal Toxicitymentioning

confidence: 96%

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Maxwell

Cole

2017

Curr Hematol Malig Rep

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Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

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“…A recent study has also provided evidence that TPMT activity may be significantly influenced by PACSIN2 [77], possibly through the latter protein's postulated role in autophagy [78]. RBC TPMT activity was found to be significantly lower in TPMT*1 homozygotes who were heterozygous or homozygous for the minor allele of PACSIN2 SNP rs2413739 (p = 0.031).…”

Section: Do Polymorphisms In Mthfr and Pascin2mentioning

confidence: 96%

“…The PACSIN2 SNP rs2413739 explained 1.8% of the variability in TPMT activity in acute lymphoblastic leukemia patients with a wild-type TPMT genotype, and 31% of the variability in patients who were TPMT*3 heterozygotes [77]. In addition, PACSIN2 SNP rs2413739 was significantly associated with severe gastrointestinal (GI) toxicity in TPMT*1 homozygotes receiving consolidation therapy comprising methotrexate and 6-MP [77] for treatment of acute lymphoblastic leukemia. However, a subsequent study found no evidence of association of PACSIN2 with overall thiopurine-related toxicity in IBD patients (p = 0.378, OR: 0.88, 95% CI: 0.67-1.…”

Section: Do Polymorphisms In Mthfr and Pascin2mentioning

confidence: 99%

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

Roberts

Barclay

2015

Pharmacogenomics

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Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

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PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity

Cited by 56 publications

References 42 publications

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

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